diff --git a/alchemiscale/interface/api.py b/alchemiscale/interface/api.py
index 8a629c2f..3165c58a 100644
--- a/alchemiscale/interface/api.py
+++ b/alchemiscale/interface/api.py
@@ -116,7 +116,14 @@ def create_network(
     validate_scopes(scope, token)
 
     an = AlchemicalNetwork.from_dict(network)
-    an_sk = n4js.create_network(network=an, scope=scope)
+
+    try:
+        an_sk = n4js.create_network(network=an, scope=scope)
+    except ValueError as e:
+        raise HTTPException(
+            status_code=status.HTTP_422_UNPROCESSABLE_ENTITY,
+            detail=e.args[0],
+        )
 
     # create taskhub for this network
     n4js.create_taskhub(an_sk)
diff --git a/alchemiscale/interface/client.py b/alchemiscale/interface/client.py
index 2f9d00f7..47a112a3 100644
--- a/alchemiscale/interface/client.py
+++ b/alchemiscale/interface/client.py
@@ -29,6 +29,7 @@
 from ..storage.models import Task, ProtocolDAGResultRef, TaskStatusEnum
 from ..strategies import Strategy
 from ..security.models import CredentialedUserIdentity
+from ..validators import validate_network_nonself
 
 
 class AlchemiscaleClientError(AlchemiscaleBaseClientError):
@@ -116,6 +117,8 @@ def create_network(
                 f"`scope` '{scope}' contains wildcards ('*'); `scope` must be *specific*"
             )
 
+        validate_network_nonself(network)
+
         from rich.progress import Progress
 
         sk = self.get_scoped_key(network, scope)
diff --git a/alchemiscale/storage/statestore.py b/alchemiscale/storage/statestore.py
index 0f62f7ca..e287948b 100644
--- a/alchemiscale/storage/statestore.py
+++ b/alchemiscale/storage/statestore.py
@@ -36,6 +36,7 @@
 
 from ..security.models import CredentialedEntity
 from ..settings import Neo4jStoreSettings, get_neo4jstore_settings
+from ..validators import validate_network_nonself
 
 
 @lru_cache()
@@ -610,6 +611,7 @@ def create_network(self, network: AlchemicalNetwork, scope: Scope):
         some of its components already exist in the database.
 
         """
+        validate_network_nonself(network)
 
         ndict = network.to_shallow_dict()
 
diff --git a/alchemiscale/tests/unit/test_validators.py b/alchemiscale/tests/unit/test_validators.py
new file mode 100644
index 00000000..ba210e3d
--- /dev/null
+++ b/alchemiscale/tests/unit/test_validators.py
@@ -0,0 +1,64 @@
+import pytest
+
+from openfe_benchmarks import tyk2
+from gufe import ChemicalSystem, Transformation, AlchemicalNetwork
+from gufe.tests.test_protocol import DummyProtocol, BrokenProtocol
+
+from alchemiscale import validators
+
+
+@pytest.fixture(scope="session")
+def network_self_transformation():
+    tyk2s = tyk2.get_system()
+    ligand = tyk2s.ligand_components[0]
+
+    cs = ChemicalSystem(
+        components={"ligand": ligand, "solvent": tyk2s.solvent_component},
+        name=f"{ligand.name}_water",
+    )
+
+    tf = Transformation(
+        stateA=cs,
+        stateB=cs,
+        protocol=DummyProtocol(settings=DummyProtocol.default_settings()),
+        name=f"{ligand.name}->{ligand.name}_water",
+    )
+
+    return AlchemicalNetwork(edges=[tf], name="self_transformation")
+
+
+@pytest.fixture(scope="session")
+def network_nonself_transformation():
+    tyk2s = tyk2.get_system()
+    ligand = tyk2s.ligand_components[0]
+    ligand2 = tyk2s.ligand_components[1]
+
+    cs = ChemicalSystem(
+        components={"ligand": ligand, "solvent": tyk2s.solvent_component},
+        name=f"{ligand.name}_water",
+    )
+
+    cs2 = ChemicalSystem(
+        components={"ligand": ligand2, "solvent": tyk2s.solvent_component},
+        name=f"{ligand2.name}_water",
+    )
+
+    tf = Transformation(
+        stateA=cs,
+        stateB=cs2,
+        protocol=DummyProtocol(settings=DummyProtocol.default_settings()),
+        name=f"{ligand.name}->{ligand2.name}_water",
+    )
+
+    return AlchemicalNetwork(edges=[tf], name="nonself_transformation")
+
+
+def test_validate_network_nonself(
+    network_self_transformation, network_nonself_transformation
+):
+    with pytest.raises(ValueError, match="uses the same `ChemicalSystem`"):
+        validators.validate_network_nonself(network_self_transformation)
+
+    out = validators.validate_network_nonself(network_nonself_transformation)
+
+    assert out is None
diff --git a/alchemiscale/validators.py b/alchemiscale/validators.py
new file mode 100644
index 00000000..0b9ba2b9
--- /dev/null
+++ b/alchemiscale/validators.py
@@ -0,0 +1,22 @@
+"""
+:mod:`alchemiscale.validators` --- validation guardrails for user input
+=======================================================================
+
+"""
+
+from gufe import AlchemicalNetwork, Transformation
+
+
+def validate_network_nonself(network: AlchemicalNetwork):
+    """Check that the given AlchemicalNetwork features no Transformations with
+    the same ChemicalSystem for its two states.
+
+    A ``ValueError`` is raised if a `Transformation` is detected.
+
+    """
+    for transformation in network.edges:
+        if transformation.stateA == transformation.stateB:
+            raise ValueError(
+                f"`Transformation` '{transformation.key}' uses the same `ChemicalSystem` '{transformation.stateA.key}' for both states; "
+                "this is currently not supported in `alchemiscale`"
+            )