Information-processing in the prefrontal cortex is abnormal in patients with schizophrenia. From functional neuroimaging and other studies, it appears that neurons of the dorsolateral prefrontal cortex are effectors of core clinical and biological phenomena associated with the illness. Cognitive deficits qualitatively similar to those in patients with schizophrenia are also found in their healthy siblings and other relatives. The evidence for abnormal prefrontal function in healthy siblings suggests that the deficit in information-processing is part of the biology of genetic susceptibility. Therefore, genetic variations in human DNA that affect this kind of information-processing may contribute part of the genetic risk for the illness. COMT is an enzyme that is distributed widely throughout the brain, but seems to be uniquely relevant to how dopamine affects information-processing in the prefrontal cortex. There is a common variation in the genetic sequence of the COMT gene, which causes a dramatic change in its enzyme activity. In people with schizophrenia, in their healthy siblings, and also in normal controls, the COMT genotype predicts 4% of the variation in human executive cognition and working memory. We have thus identified a genetic mechanism in the human species that affects the efficiency and efficacy of information-processing in the prefrontal cortex. It is, also, a weak genetic risk factor for schizophrenia: in family studies, it increases the risk of schizophrenia by 50-80%. Prefrontal neuronal tuning may be a target for new drug development in the future.