Stress-restress evokes a complex neurobiological response in the hippocampus involving neuro-excitatory and neurotoxic pathways, as well as neuroinhibitory and neuroprotective responses to chronic stress.One of these changes involves a long-lasting increase in hippocampal iNOS activity that is accompanied by a reactive downregulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. These perturbations may have importance in explaining the increasing evidence for stress-related hippocampal degenerative pathology and cognitive deficits seen in patients with PTSD. Nitric oxide thus plays a major role in the pathophysiology of PTSD, thus presenting an area of major therapeutic opportunity for this mental illness.