Many of the symptoms of schizophrenia appear to involve dysfunction of the cognitive processes mediated by the neural circuitry of the cerebral cortex. The application of modern neuroscience techniques to the study of postmortem human brain specimens provides a powerful approach for exploring the manner in which cortical circuitry may be disrupted in schizophrenia. In this paper, we describe a strategy for the conduct of postmortem investigations of schizophrenia that involves (1) the use of a nonhuman primate model to guide the design and interpretation of studies in humans; (2) the detailed characterization of the normal organization of neural systems in the human cerebral cortex, and the range of inter-individual variations in that organization; and (3) the testing of specific hypotheses about the disruption of that organization in schizophrenia. The application of this strategy, and its value in overcoming some of the potential pitfalls of postmortem studies, is demonstrated in a series of investigations designed to test the hypothesis that dopamine neurotransmission is impaired in the entorhinal cortex in schizophrenia.