Schizophrenia is a chronic, severely disabling brain disorder with symptomatic onset in early adulthood. Typical antipsychotic medications that block dopamine D2 receptors are most effective in treating the psychosis but have limited effects on the negative symptoms and cognitive impairments. Considerable research has demonstrated that noncompetitive NMDA receptor antagonists, the dissociative anaesthetic like phencyclidine and ketamine, reproduce the cardinal symptomatic features of schizophrenia. Postmortem studies reveal variable alterations in glutamate receptors and their modulators in schizophrenia. Several clinical trials indicate agents that enhance NMDA receptor function via the glycine modulatory site reduce negative and variably improve cognitive function in schizophrenics receiving typical antipsychotics. Thus, hypofunction of a subpopulation of cortico-limbic NMDA receptors may participate in the pathophysiology of schizophrenia.