Schizophrenia remains a disabling disorder despite 50 years of antipsychotic drug development focused on the dopamine D2 receptor. Recent studies suggest that NMDA receptor hypofunction may contribute to schizophrenia symptoms, including negative symptoms and cognitive impairments. Low-dose NMDA receptor antagonists induce symptoms similar to those in schizophrenia in normal subjects. Genetic studies identify risk genes for schizophrenia that affect NMDA receptor function or glutamatergic neurotransmission. Placebo-controlled trials with agents that activate the glycine modulatory site on the NMDA receptor show reductions in negative symptoms and improvements in cognition in schizophrenia patients. NMDA receptor hypofunction, possibly involving GABAergic interneurons, may contribute to the pathophysiology of schizophrenia. The NMDA receptor is central to synaptic plasticity and its dysfunction can lead to oxidative stress and neuronal death. Astrocytes play a key role in regulating NMDA receptor function. NMDA receptor hypofunction is supported by studies in NMDA receptor antagonist studies, brain imaging, genetic, postmortem, and pharmacologic interventions. The ketamine challenge strategy reproduces schizophrenia-like symptoms in normal subjects. Event-related brain potentials (ERPs) show abnormalities in schizophrenia patients, indicating NMDA receptor dysfunction. Neuropathology studies reveal reduced GABAergic function in schizophrenia, possibly due to NMDA receptor hypofunction. Imaging studies show structural brain changes in schizophrenia, including enlarged lateral ventricles and reduced prefrontal cortex volume. Genetic studies identify risk genes for schizophrenia, including COMT, Dysbindin, Neuregulin, RGS4, DISC1, GRM3, and G72. These genes are associated with glutamatergic neurotransmission and NMDA receptor function. The glycine modulatory site (GMS) on the NMDA receptor is a potential therapeutic target. Pharmacologic studies show that agents that enhance NMDA receptor function, such as D-cycloserine, glycine, and D-serine, can reduce schizophrenia symptoms. Clozapine, an atypical antipsychotic, has unique effects on schizophrenia patients and may enhance NMDA receptor function. The evidence supports the hypothesis that NMDA receptor hypofunction contributes to schizophrenia symptoms, particularly the endophenotype. Enhancing NMDA receptor function may offer a more effective treatment for schizophrenia symptoms that are resistant to dopamine D2 receptor-directed therapy. The role of glutamate and NMDA receptors in schizophrenia is increasingly recognized as a key factor in the disorder's pathophysiology.Schizophrenia remains a disabling disorder despite 50 years of antipsychotic drug development focused on the dopamine D2 receptor. Recent studies suggest that NMDA receptor hypofunction may contribute to schizophrenia symptoms, including negative symptoms and cognitive impairments. Low-dose NMDA receptor antagonists induce symptoms similar to those in schizophrenia in normal subjects. Genetic studies identify risk genes for schizophrenia that affect NMDA receptor function or glutamatergic neurotransmission. Placebo-controlled trials with agents that activate the glycine modulatory site on the NMDA receptor show reductions in negative symptoms and improvements in cognition in schizophrenia patients. NMDA receptor hypofunction, possibly involving GABAergic interneurons, may contribute to the pathophysiology of schizophrenia. The NMDA receptor is central to synaptic plasticity and its dysfunction can lead to oxidative stress and neuronal death. Astrocytes play a key role in regulating NMDA receptor function. NMDA receptor hypofunction is supported by studies in NMDA receptor antagonist studies, brain imaging, genetic, postmortem, and pharmacologic interventions. The ketamine challenge strategy reproduces schizophrenia-like symptoms in normal subjects. Event-related brain potentials (ERPs) show abnormalities in schizophrenia patients, indicating NMDA receptor dysfunction. Neuropathology studies reveal reduced GABAergic function in schizophrenia, possibly due to NMDA receptor hypofunction. Imaging studies show structural brain changes in schizophrenia, including enlarged lateral ventricles and reduced prefrontal cortex volume. Genetic studies identify risk genes for schizophrenia, including COMT, Dysbindin, Neuregulin, RGS4, DISC1, GRM3, and G72. These genes are associated with glutamatergic neurotransmission and NMDA receptor function. The glycine modulatory site (GMS) on the NMDA receptor is a potential therapeutic target. Pharmacologic studies show that agents that enhance NMDA receptor function, such as D-cycloserine, glycine, and D-serine, can reduce schizophrenia symptoms. Clozapine, an atypical antipsychotic, has unique effects on schizophrenia patients and may enhance NMDA receptor function. The evidence supports the hypothesis that NMDA receptor hypofunction contributes to schizophrenia symptoms, particularly the endophenotype. Enhancing NMDA receptor function may offer a more effective treatment for schizophrenia symptoms that are resistant to dopamine D2 receptor-directed therapy. The role of glutamate and NMDA receptors in schizophrenia is increasingly recognized as a key factor in the disorder's pathophysiology.