Frontal lobe and basal ganglia lesions have been associated with similar cognitive impairments, although their specialized roles in behavior are likely to be different. We examined whether these structures mediate distinctive or overlapping aspects of a complex behavioral process that has been associated with both neural sites, i.e. cognitive flexibility. Patients with focal ischemic lesions to the frontal lobe and basal ganglia were compared on two forms of cognitive flexibility: (1) shifting response set (i.e. reactive flexibility), and (2) producing a diversity of ideas (i.e. spontaneous flexibility). Results indicated that frontal lobe and basal ganglia damage each caused a similar degree of impairment in reactive flexibility, both groups performing at a significantly lower level than posterior cortical lesion and normal comparison groups. However, frontal lobe damage markedly disturbed spontaneous flexibility, while performance after basal ganglia lesion was significantly higher and comparable to posterior cortical lesions. Findings suggest that the frontal lobe and basal ganglia participate differently in the neural substrate of cognitive flexibility. The frontal lobe appears to mediate spontaneous flexibility. The production of diverse ideas may require direct cortical-cortical interactions by the frontal lobe in order to access knowledge systems with novel strategies that transcend the most common semantic linkages. In contrast the corticostriate system appears to mediate reactive flexibility, as the frontal lobe, basal ganglia and their interconnections are required for its operation.