To determine the neural circuitry engaged by performance of the Wisconsin Card Sorting Test (WCST), a neuropsychological test traditionally considered to be sensitive to prefrontal lesions, regional cerebral blood flow was measured with oxygen-15 water and positron emission tomography (PET) while young normal subjects performed the test as well as while they performed a specially designed sensorimotor control task. To consider which of the various cognitive operations and other experiential phenomena involved in the WCST PET scan are critical for the pattern of physiological activation and to focus on the working memory component of the test, repeat WCST scans were also performed on nine of the subjects after instruction on the test and practice to criteria. We confirmed that performance of the WCST engages the frontal cortex and also produces activation of a complex network of regions consistently including the inferior parietal lobule but also involving the visual association and inferior temporal cortices as well as portions of the cerebellum. The WCST activation in the dorsolateral prefrontal cortex (DLPFC) remained significant even after training and practice on the test, suggesting that working memory may be largely responsible for the physiological response in DLPFC during the WCST and, conversely, that the DLPFC plays a major role in modulating working memory.