This article reviews prefrontal cortical biology as it relates to pathophysiology and genetic risk for schizophrenia. Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. 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-methyl transferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. The 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 mechanism for a genetic effect on normal human cognition and risk for mental illness.