A non-classical neurotransmitter is a substance that effects the functioning of neurons through means other then excitation or inhibition across a synapse. It is sometimes also applied to polypeptides or amino acids that function as neurotransmitters.

Of course, by this definition, water and glucose could be considered non-classical neurotransmitters. In practice, however, the substance has to have a sufficient modifying effect that works specifically on nerve cells to be considered as such.

A non-classical neurotransmitter could be something as diverse as a protein that encourages nerve cells to grow or branch; a hormone that allows blood vessels to allow more ions into the CNS, a chemical that modifies the Krebs Cycle and thus the amount of energy present in the cell. In other words, almost anything.

Examples of important non-classical neurotransmitter is adenosine, melatonin and Nitric Oxide.