Endogenous nitric oxide (NO) mediates certain aspects of synaptic plasticity and neurotoxicity associated with NMDA-type glutamate receptors. Neuronal NO synthase contains a modular protein-protein interaction motif, termed the PDZ domain, that links the synthase to a synaptic protein complex containing postsynaptic density protein PSD-95 and NMDA receptors. Characterization of this pathway has provided new insights into the role of NO in brain physiology and disease.