Several lines of evidence suggest that schizophrenia is associated with three major neurochemical imbalances: an excess of subcortical dopamine (DA) transmission at D2 receptors, a deficit of prefrontal DA transmission at D1 receptors, and a deficiency of glutamate transmission at the n-methyl-D-aspartate (NMDA) receptor. The lecture will present recent advances in human imaging studies, that enabled bridging the dopamine and NMDA hypothesis of schizophrenia into one conceptual framework: 1) Under conditions of enhanced DA activity, such as following amphetamine challenge, blockade of NMDA transmission in healthy volunteers results in excess amphetamine-induced DA release. 2) Chronic exposure to NMDA antagonists lead to deficit in prefrontal DA and subsequent upregulation of D1 receptors in both animals and humans. These data are consistent with the hypothesis that, in schizophrenia, NMDA receptor hypofunction might be mechanism leading to the observed DA imbalance. If sustained, this DA imbalance leads to emergence of neuronal loops within cortical-striatal-thalamic-cortical circuits that underlie the psychotic experience. This model has several implications for the development of better treatments for this devastating illness.