This review describes a research program aimed at evaluating the validity and specificity of the Wisconsin Card Sorting Test (WCST), one of the most widely used tests of prefrontal function in clinical and experimental neuropsychology. In spite of its extensive use, voices of caution have arisen against the use of WCST scores as direct markers of prefrontal damage or dysfunction. Adopting a cognitive neuroscience approach, the present research program integrates behavioral, physiological, and anatomical information to investigate the cognitive and neural mechanisms behind WCST performance. The results show that WCST performance evokes conspicuous physiological changes over frontal as well as posterior brain regions. Moreover, WCST scores confound very heterogeneous cognitive and neural processes. This confounding effect may have led many authors to overlook the relative importance of certain dysfunctional states such as those indexed by random errors. These findings strongly suggest that WCST scores cannot be regarded as valid nor specific markers of prefrontal lobe function. However, they do provide some relevant clues to update our current knowledge about prefrontal function. In the long run, the integrative approach of cognitive neuroscience may help us design and develop more valid and sensitive tools for neuropsychological assessment.