diff --git a/.github/workflows/ci.yml b/.github/workflows/ci.yml
index 03bf8f4e..f5a7e9ce 100644
--- a/.github/workflows/ci.yml
+++ b/.github/workflows/ci.yml
@@ -15,7 +15,7 @@ jobs:
     runs-on: ubuntu-latest
     strategy:
       matrix:
-        python-version: ["3.10"]
+        python-version: ["3.11"]
 
     steps:
     - uses: actions/checkout@v2
@@ -35,7 +35,7 @@ jobs:
     runs-on: ubuntu-latest
     strategy:
       matrix:
-        python-version: ["3.10"]
+        python-version: ["3.11"]
 
     steps:
     - uses: actions/checkout@v2
@@ -56,7 +56,7 @@ jobs:
     runs-on: ubuntu-latest
     strategy:
       matrix:
-        python-version: ["3.10"]
+        python-version: ["3.11"]
 
     steps:
     - uses: actions/checkout@v2
@@ -77,7 +77,7 @@ jobs:
     runs-on: ubuntu-latest
     strategy:
       matrix:
-        python-version: ["3.10"]
+        python-version: ["3.11"]
         devices: ["1", "2", "3"]
 
     env:
@@ -101,7 +101,7 @@ jobs:
     runs-on: ubuntu-latest
     strategy:
       matrix:
-        python-version: ["3.10"]
+        python-version: ["3.11"]
         devices: ["1", "2", "3"]
 
     env:
@@ -125,7 +125,7 @@ jobs:
     runs-on: ubuntu-latest
     strategy:
       matrix:
-        python-version: ["3.10"]
+        python-version: ["3.11"]
 
     steps:
     - uses: actions/checkout@v2
diff --git a/.github/workflows/pypi.yml b/.github/workflows/pypi.yml
index 4e3249b3..b76aae8e 100644
--- a/.github/workflows/pypi.yml
+++ b/.github/workflows/pypi.yml
@@ -22,7 +22,7 @@ jobs:
     - name: Set up Python
       uses: actions/setup-python@v3
       with:
-        python-version: "3.10"
+        python-version: "3.11"
     - name: Install dependencies
       run: |
         python -m pip install --upgrade pip
diff --git a/.github/workflows/testpypi.yml b/.github/workflows/testpypi.yml
index cfc99a27..ea0b7a85 100644
--- a/.github/workflows/testpypi.yml
+++ b/.github/workflows/testpypi.yml
@@ -22,7 +22,7 @@ jobs:
     - name: Set up Python
       uses: actions/setup-python@v3
       with:
-        python-version: "3.10"
+        python-version: "3.11"
     - name: Install dependencies
       run: |
         python -m pip install --upgrade pip
diff --git a/README.rst b/README.rst
index 8df23d8b..f5ecac93 100644
--- a/README.rst
+++ b/README.rst
@@ -1,5 +1,5 @@
 .. image:: https://cellarium.ai/wp-content/uploads/2024/07/cellarium-logo-medium.png
-   :alt: Cellarium Logo
+   :alt: Cellarium Logo!!
    :width: 180
    :align: center
 
diff --git a/cellarium/ml/data/distributed_anndata.py b/cellarium/ml/data/distributed_anndata.py
index 60eae53b..4cf92b4e 100644
--- a/cellarium/ml/data/distributed_anndata.py
+++ b/cellarium/ml/data/distributed_anndata.py
@@ -18,7 +18,7 @@
 from boltons.cacheutils import LRU
 from braceexpand import braceexpand
 
-from cellarium.ml.data.fileio import read_h5ad_file
+from cellarium.ml.data.fileio import backed_mode_default, backed_mode_type, read_h5ad_file
 from cellarium.ml.data.schema import AnnDataSchema
 
 
@@ -28,6 +28,8 @@ class getattr_mode:
 
 _GETATTR_MODE = getattr_mode()
 
+allowed_backed_modes = [None, True, False, "r"]
+
 
 @contextmanager
 def lazy_getattr():
@@ -155,6 +157,12 @@ class DistributedAnnDataCollection(AnnCollection):
         obs_columns_to_validate:
             Subset of columns to validate in the :attr:`obs` attribute.
             If ``None``, all columns are validated.
+        backed:
+            Optional backing mode for the h5ad files. ``'r'`` will leave count matrices
+            on disk until specific cell indices are queried, enabling the use of very large
+            h5ad files, while ``None`` will load entire count matrices from individual h5ad files
+            into cached memory as needed: a strategy that necessitates smaller chunked h5ad files.
+            See :func:`anndata.read_h5ad` for details on backing modes.
     """
 
     def __init__(
@@ -171,6 +179,7 @@ def __init__(
         convert: ConvertType | None = None,
         indices_strict: bool = True,
         obs_columns_to_validate: Sequence[str] | None = None,
+        backed: backed_mode_type = backed_mode_default,
     ):
         self.filenames = list(braceexpand(filenames) if isinstance(filenames, str) else filenames)
         if (shard_size is None) and (last_shard_size is not None):
@@ -192,8 +201,11 @@ def __init__(
         self.cache = LRU(max_cache_size)
         self.max_cache_size = max_cache_size
         self.cache_size_strictly_enforced = cache_size_strictly_enforced
+        if backed not in allowed_backed_modes:
+            raise ValueError(f"Invalid backed mode: {backed}. Choose from {allowed_backed_modes}")
+        self.backed = backed
         # schema
-        adata0 = self.cache[self.filenames[0]] = read_h5ad_file(self.filenames[0])
+        adata0 = self.cache[self.filenames[0]] = read_h5ad_file(self.filenames[0], backed=backed)
         if len(adata0) != limits[0]:
             raise ValueError(
                 f"The number of cells in the first anndata file ({len(adata0)}) "
@@ -203,7 +215,7 @@ def __init__(
         self.schema = AnnDataSchema(adata0, obs_columns_to_validate)
         # lazy anndatas
         lazy_adatas = [
-            LazyAnnData(filename, (start, end), self.schema, self.cache)
+            LazyAnnData(filename, (start, end), self.schema, self.cache, backed=backed)
             for start, end, filename in zip([0] + limits, limits, self.filenames)
         ]
         # use filenames as default keys
@@ -298,10 +310,10 @@ def __getstate__(self):
     def __setstate__(self, state):
         self.__dict__.update(state)
         self.cache = LRU(self.max_cache_size)
-        adata0 = self.cache[self.filenames[0]] = read_h5ad_file(self.filenames[0])
+        adata0 = self.cache[self.filenames[0]] = read_h5ad_file(self.filenames[0], backed=self.backed)
         self.schema = AnnDataSchema(adata0, self.obs_columns_to_validate)
         self.adatas = [
-            LazyAnnData(filename, (start, end), self.schema, self.cache)
+            LazyAnnData(filename, (start, end), self.schema, self.cache, backed=self.backed)
             for start, end, filename in zip([0] + self.limits, self.limits, self.filenames)
         ]
         self.obs_names = pd.Index([f"cell_{i}" for i in range(self.limits[-1])])
@@ -323,6 +335,11 @@ class LazyAnnData:
             Schema used as a reference for lazy attributes.
         cache:
             Shared LRU cache storing buffered anndatas.
+        backed:
+            Optional backing mode for the anndata. ``'r'`` will leave count matrix
+            on disk, while ``None`` will load count matrix in memory (when the anndata is
+            cached by calling the `.adata` property).
+            See :func:`anndata.read_h5ad` for details on backing modes.
     """
 
     _lazy_attrs = ["obs", "obsm", "layers", "var", "varm", "varp", "var_names"]
@@ -343,10 +360,14 @@ def __init__(
         limits: tuple[int, int],
         schema: AnnDataSchema,
         cache: LRU | None = None,
+        backed: backed_mode_type = backed_mode_default,
     ):
         self.filename = filename
         self.limits = limits
         self.schema = schema
+        if backed not in allowed_backed_modes:
+            raise ValueError(f"Invalid backed mode: {backed}. Choose from {allowed_backed_modes}")
+        self.backed = backed
         if cache is None:
             cache = LRU()
         self.cache = cache
@@ -382,16 +403,16 @@ def cached(self) -> bool:
 
     @property
     def adata(self) -> AnnData:
-        """Return backed anndata from the filename"""
+        """Return anndata from the filename"""
         try:
             adata = self.cache[self.filename]
         except KeyError:
             # fetch anndata
-            adata = read_h5ad_file(self.filename)
+            adata = read_h5ad_file(self.filename, backed=self.backed)
             # validate anndata
             if self.n_obs != adata.n_obs:
                 raise ValueError(
-                    "Expected `n_obs` for LazyAnnData object and backed anndata to match "
+                    "Expected `n_obs` for LazyAnnData object and loaded anndata to match "
                     f"but found {self.n_obs} and {adata.n_obs}, respectively."
                 )
             self.schema.validate_anndata(adata)
@@ -426,8 +447,9 @@ def __repr__(self) -> str:
             buffered = "Cached "
         else:
             buffered = ""
-        backed_at = f" backed at {str(self.filename)!r}"
-        descr = f"{buffered}LazyAnnData object with n_obs × n_vars = {self.n_obs} × {self.n_vars}{backed_at}"
+        located_at = f" referencing {str(self.filename)!r}"
+        backed = " in backed mode" if (self.backed in [True, "r"]) else " in memory mode"
+        descr = f"{buffered}LazyAnnData object with n_obs × n_vars = {self.n_obs} × {self.n_vars}{located_at}{backed}"
         if self.cached:
             for attr in self._all_attrs:
                 keys = getattr(self, attr).keys()
diff --git a/cellarium/ml/data/fileio.py b/cellarium/ml/data/fileio.py
index c1a3229e..01a3c1c6 100644
--- a/cellarium/ml/data/fileio.py
+++ b/cellarium/ml/data/fileio.py
@@ -1,18 +1,26 @@
 # Copyright Contributors to the Cellarium project.
 # SPDX-License-Identifier: BSD-3-Clause
 
+import os
 import re
 import shutil
 import tempfile
 import urllib.request
+from typing import Literal
 
 from anndata import AnnData, read_h5ad
 from google.cloud.storage import Client
 
 url_schemes = ("http:", "https:", "ftp:")
+backed_mode_type = Literal["r"] | bool | None
+backed_mode_default: backed_mode_type = "r"
 
 
-def read_h5ad_gcs(filename: str, storage_client: Client | None = None) -> AnnData:
+def read_h5ad_gcs(
+    filename: str,
+    storage_client: Client | None = None,
+    backed: backed_mode_type = backed_mode_default,
+) -> AnnData:
     r"""
     Read ``.h5ad``-formatted hdf5 file from the Google Cloud Storage.
 
@@ -22,6 +30,9 @@ def read_h5ad_gcs(filename: str, storage_client: Client | None = None) -> AnnDat
 
     Args:
         filename: Path to the data file in Cloud Storage.
+        backed: See :func:`anndata.read_h5ad` for details on backed mode.
+            ['r', True] will load in backed mode instead of fully loading into memory.
+            [False, None] will use in-memory mode.
     """
     if not filename.startswith("gs:"):
         raise ValueError("The filename must start with 'gs:' protocol name.")
@@ -35,11 +46,20 @@ def read_h5ad_gcs(filename: str, storage_client: Client | None = None) -> AnnDat
     bucket = storage_client.bucket(bucket_name)
     blob = bucket.blob(blob_name)
 
-    with blob.open("rb") as f:
-        return read_h5ad(f)
+    # write to a named temporary file
+    with tempfile.NamedTemporaryFile(suffix=".h5ad", delete=False) as tmp_file:
+        temp_path = tmp_file.name
+        blob.download_to_file(tmp_file)
+        try:
+            return read_h5ad(temp_path, backed=backed)
+        finally:
+            try:
+                os.unlink(temp_path)  # clean up the temp file
+            except OSError:
+                pass  # if there's an error during cleanup, continue
 
 
-def read_h5ad_url(filename: str) -> AnnData:
+def read_h5ad_url(filename: str, backed: backed_mode_type = backed_mode_default) -> AnnData:
     r"""
     Read ``.h5ad``-formatted hdf5 file from the URL.
 
@@ -48,37 +68,59 @@ def read_h5ad_url(filename: str) -> AnnData:
         >>> adata = read_h5ad_url(
         ...     "https://storage.googleapis.com/dsp-cellarium-cas-public/test-data/test_0.h5ad"
         ... )
+        >>> adata = read_h5ad_url(
+        ...     "https://storage.googleapis.com/dsp-cellarium-cas-public/test-data/test_0.h5ad",
+        ...     backed='r'
+        ... )
 
     Args:
         filename: URL of the data file.
+        backed: See :func:`anndata.read_h5ad` for details on backed mode.
+            ['r', True] will load in backed mode instead of fully loading into memory.
+            [False, None] will use in-memory mode.
     """
     if not any(filename.startswith(scheme) for scheme in url_schemes):
         raise ValueError("The filename must start with 'http:', 'https:', or 'ftp:' protocol name.")
-    with urllib.request.urlopen(filename) as response:
-        with tempfile.TemporaryFile() as tmp_file:
+
+    # write to a named temporary file
+    with tempfile.NamedTemporaryFile(suffix=".h5ad", delete=False) as tmp_file:
+        temp_path = tmp_file.name
+        with urllib.request.urlopen(filename) as response:
             shutil.copyfileobj(response, tmp_file)
-            return read_h5ad(tmp_file)
+        try:
+            return read_h5ad(temp_path, backed=backed)
+        finally:
+            try:
+                os.unlink(temp_path)  # clean up the temp file
+            except OSError:
+                pass  # if there's an error during cleanup, continue
 
 
-def read_h5ad_local(filename: str) -> AnnData:
+def read_h5ad_local(filename: str, backed: backed_mode_type = backed_mode_default) -> AnnData:
     r"""
     Read ``.h5ad``-formatted hdf5 file from the local disk.
 
     Args:
         filename: Path to the local data file.
+        backed: See :func:`anndata.read_h5ad` for details on backed mode.
+            ['r', True] will load in backed mode instead of fully loading into memory.
+            [False, None] will use in-memory mode.
     """
     if not filename.startswith("file:"):
         raise ValueError("The filename must start with 'file:' protocol name.")
     filename = re.sub(r"^file://?", "", filename)
-    return read_h5ad(filename)
+    return read_h5ad(filename, backed=backed)
 
 
-def read_h5ad_file(filename: str, **kwargs) -> AnnData:
+def read_h5ad_file(filename: str, backed: backed_mode_type = backed_mode_default, **kwargs) -> AnnData:
     r"""
     Read ``.h5ad``-formatted hdf5 file from a filename.
 
     Args:
         filename: Path to the data file.
+        backed: See :func:`anndata.read_h5ad` for details on backed mode.
+            ['r', True] will load in backed mode instead of fully loading into memory.
+            [False, None] will use in-memory mode.
     """
     if filename.startswith("gs:"):
         return read_h5ad_gcs(filename, **kwargs)
@@ -89,4 +131,4 @@ def read_h5ad_file(filename: str, **kwargs) -> AnnData:
     if any(filename.startswith(scheme) for scheme in url_schemes):
         return read_h5ad_url(filename)
 
-    return read_h5ad(filename)
+    return read_h5ad(filename, backed=backed)
diff --git a/pyproject.toml b/pyproject.toml
index b361431c..682d12a9 100644
--- a/pyproject.toml
+++ b/pyproject.toml
@@ -10,7 +10,7 @@ authors = [
 ]
 description = "Machine learning library for single-cell data analysis"
 readme = "README.rst"
-requires-python = ">=3.10"
+requires-python = ">=3.11"
 license = {file = "LICENSE.md"}
 classifiers = [
   "Intended Audience :: Developers",
@@ -21,7 +21,7 @@ classifiers = [
 ]
 
 dependencies = [
-  "anndata",
+  "anndata @ git+https://github.com/sjfleming/anndata.git@sf-backed-hdf5-fancy-indexing",
   "boltons",
   "braceexpand",
   "crick>=0.0.4",
diff --git a/tests/dataloader/test_datamodule.py b/tests/dataloader/test_datamodule.py
index 8923872f..e7acd85c 100644
--- a/tests/dataloader/test_datamodule.py
+++ b/tests/dataloader/test_datamodule.py
@@ -2,6 +2,7 @@
 # SPDX-License-Identifier: BSD-3-Clause
 
 from pathlib import Path
+from typing import Any
 
 import lightning.pytorch as pl
 import pytest
@@ -176,14 +177,15 @@ def _check_transform_lists_match(iterable_modules1, iterable_modules2, message):
     "accelerator",
     ["cpu", pytest.param("gpu", marks=pytest.mark.skipif(not USE_CUDA, reason="requires_cuda"))],
 )
-@pytest.mark.parametrize("batch_size", [50, None])
-def test_datamodule(tmp_path: Path, batch_size: int | None, accelerator: str) -> None:
+@pytest.mark.parametrize("batch_size", [50, 100])
+def test_datamodule(tmp_path: Path, batch_size: int, accelerator: str) -> None:
+    dadc = DistributedAnnDataCollection(
+        filenames="https://storage.googleapis.com/dsp-cellarium-cas-public/test-data/test_0.h5ad",
+        shard_size=100,
+    )
     datamodule = CellariumAnnDataDataModule(
-        DistributedAnnDataCollection(
-            filenames="https://storage.googleapis.com/dsp-cellarium-cas-public/test-data/test_0.h5ad",
-            shard_size=100,
-        ),
-        batch_size=100,
+        dadc=dadc,
+        batch_size=batch_size,
         batch_keys={
             "x_ng": AnnDataField(attr="X", convert_fn=densify),
         },
@@ -193,15 +195,76 @@ def test_datamodule(tmp_path: Path, batch_size: int | None, accelerator: str) ->
     trainer.fit(module, datamodule)
 
     ckpt_path = str(tmp_path / "lightning_logs/version_0/checkpoints/epoch=0-step=1.ckpt")
-    adata = datamodule.dadc.adatas[0].adata
-    kwargs = {"dadc": adata}
+    kwargs: dict[str, Any] = {"dadc": dadc}
     if batch_size is not None:
         kwargs["batch_size"] = batch_size
     loaded_datamodule = CellariumAnnDataDataModule.load_from_checkpoint(ckpt_path, **kwargs)
 
     assert loaded_datamodule.batch_keys == datamodule.batch_keys
     assert loaded_datamodule.batch_size == batch_size or datamodule.batch_size
-    assert loaded_datamodule.dadc is adata
+    assert loaded_datamodule.dadc is dadc
+
+
+@pytest.fixture
+def fake_massive_dense_h5ad(tmp_path: Path) -> Path:
+    import h5py
+    import numpy as np
+
+    # Create a dataset that CLAIMS to be ~40GB but uses almost no disk space
+    n_obs = 2_000_000  # 2 million cells
+    n_vars = 5_000  # 5k genes
+
+    h5ad_path = tmp_path / "massive_fake.h5ad"
+
+    with h5py.File(h5ad_path, "w") as f:
+        # Create X dataset with claimed huge size but minimal actual storage
+        # Using fillvalue=0.0 with chunking - chunks are only allocated when written to
+        f.create_dataset(
+            "X",
+            shape=(n_obs, n_vars),
+            dtype=np.float32,
+            fillvalue=0.0,
+            chunks=True,  # Enable chunking so not all data needs to be stored
+            compression=None,  # No compression to keep it simple
+        )
+
+        # Create minimal obs metadata - just the index is required
+        obs_group = f.create_group("obs")
+        # Create a small obs index but tell HDF5 it could expand to n_obs
+        obs_index_data = np.array([f"CELL_{i:07d}".encode("utf-8") for i in range(n_obs)])
+        obs_group.create_dataset("_index", data=obs_index_data, maxshape=(n_obs,), dtype="S12")
+
+        # Create minimal var metadata - just the index is required
+        var_group = f.create_group("var")
+        var_index_data = np.array([f"GENE_{i:05d}".encode("utf-8") for i in range(n_vars)])
+        var_group.create_dataset("_index", data=var_index_data, dtype="S10")
+
+        # Set minimal h5ad format attributes that anndata expects
+        f.attrs["encoding-type"] = "anndata"
+        f.attrs["encoding-version"] = "0.1.0"
+
+    return h5ad_path
+
+
+def test_datamodule_massive_h5ad_backed(tmp_path: Path, fake_massive_dense_h5ad: Path) -> None:
+    # try training using a massive (faked) h5ad file which should only succeed if backed mode works
+    dadc = DistributedAnnDataCollection(
+        filenames=str(fake_massive_dense_h5ad),  # Use full path instead of just name
+        shard_size=2_000_000,
+        backed=True,
+    )
+    datamodule = CellariumAnnDataDataModule(
+        dadc=dadc,
+        batch_size=100,
+        batch_keys={
+            "x_ng": AnnDataField(attr="X", convert_fn=None),  # already dense
+        },
+    )
+    module = CellariumModule(model=BoringModel())
+    trainer = pl.Trainer(accelerator="cpu", devices=1, max_steps=1, default_root_dir=tmp_path)
+    trainer.fit(module, datamodule)
+    # the idea is if this can run without a memory overflow, backed mode is implemented correctly
+    # we have separately verified that backed=False will crash due to 40GB memory use
 
 
 @pytest.mark.parametrize(
diff --git a/tests/dataloader/test_distributed_anndata.py b/tests/dataloader/test_distributed_anndata.py
index dad39235..4244a4c7 100644
--- a/tests/dataloader/test_distributed_anndata.py
+++ b/tests/dataloader/test_distributed_anndata.py
@@ -69,22 +69,31 @@ def adatas_path(tmp_path: Path):
 
 @pytest.fixture
 def adt(adatas_path: Path):
-    # single anndata
-    adt = read_h5ad_file(str(os.path.join(adatas_path, "adata.h5ad")))
+    # single anndata in memory
+    adt = read_h5ad_file(str(os.path.join(adatas_path, "adata.h5ad")), backed=None)
     return adt
 
 
-@pytest.fixture(params=[(i, j) for i in (1, 2, 3) for j in (True, False)])
+@pytest.fixture(
+    params=[(i, j, k) for i in (1, 2, 3) for j in (True, False) for k in (None, "r")],
+    ids=[
+        f"cache{i}-enforce{j}-{'memory' if k is None else 'backed'}"
+        for i in (1, 2, 3)
+        for j in (True, False)
+        for k in (None, "r")
+    ],
+)
 def dat(adatas_path: Path, request: pytest.FixtureRequest):
     # distributed anndata
     filenames = str(os.path.join(adatas_path, "adata.{000..002}.h5ad"))
     limits = [2, 5, 10]
-    max_cache_size, cache_size_strictly_enforced = request.param
+    max_cache_size, cache_size_strictly_enforced, backed_mode = request.param
     dat = DistributedAnnDataCollection(
         filenames,
         limits,
         max_cache_size=max_cache_size,
         cache_size_strictly_enforced=cache_size_strictly_enforced,
+        backed=backed_mode,
     )
     return dat