Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Both the physiologic abnormalities and the cognitive deficits are predicted by a cellular measure in dorsolateral prefrontal cortex–low N-acetyl-aspartate signals from magnetic resonance spectroscopy. In pharmacologic imaging studies, patients manifest excessive dopamine release induced by amphetamine, an abnormality also predicted by low N-acetyl-aspartate in the dorsolateral prefrontal cortex. These findings suggest that abnormal function of the working memory cortical system (associated with positive symptoms) represents emergent properties of specific dorsolateral prefrontal cortex neuronal pathology. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. Functional magnetic resonance imaging confirms that COMT genotype affects prefrontal physiology during working memory. Family-based association studies have revealed excessive transmission to schizophrenic offspring of the allele (Val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT Val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing, the first plausible biologic mechanism by which a specific allele affects variation in normal human cognition and risk for mental illness. These findings have implications for the development of novel treatments aimed at the prefrontal dopamine signaling cascade.