Numerous clinical studies demonstrate that subanesthetic doses of dissociative anesthetics, which are noncompetitive antagonists at the NMDA receptor, replicate in normal subjects the cognitive impairments, negative symptoms, and brain functional abnormalities of schizophrenia. Postmortem and genetic studies have identified several abnormalities associated with schizophrenia that would interfere with the activation of the glycine modulatory site on the NMDA receptor. Placebo-controlled clinical trials with agents that directly or indirectly activate the glycine modulatory site consistently reduce negative symptoms and frequently improve cognition in patients with chronic schizophrenia who are receiving concurrent typical antipsychotics. Thus, there is convincing evidence that hypofunction of a subset of NMDA receptors may contribute to the symptomatic features of schizophrenia.