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Recent evidence from studies of receptor occupancy and regulation in post-mortem brains of patients with neuropsychiatric disorders and in non-human primates is providing new leads in the ongoing quest to understand the pathophysiology and causes of schizophrenia and to develop more effective methods of treatment. These studies suggest that the cerebral cortex may harbour the elusive common sites of action of antipsychotic medications and indicate that chronic treatment with these drugs differentially regulates both families of dopamine receptors in this structure. Upregulation of the cortical dopamine D2 receptors is accompanied by a downregulation of the D1 sites. Balancing the opposing actions of dopamine D1 and D2 receptor regulation may hold the key to optimal drug therapy and to understanding the pathophysiology of schizophrenia. In this article, Michael Lidow, Graham Williams and Patricia Goldman-Rakic review the evidence supporting the cerebral cortex as a pivotal site for these mechanisms underlying the action of antipsychotics.