The prefrontal cortex is considered to provide executive control of response selection and planning in diverse cognitive tasks, translated into action via descending subcortical projections (or 'loops') through the basal ganglia. We have used a disconnection strategy to demonstrate first that bilateral fronto-striatal disconnection disrupts rats' abilities to perform delayed alternation, the classic test of prefrontal function in rats and monkeys, and second that crossed unilateral cortical and striatal lesions on opposite sides similarly disrupt rats' abilities to perform the same cognitive task. We found that effective disconnection requires interruption of interhemispheric transfer, achieved by transection of the anterior corpus callosum. This produces a moderate deficit in its own right, which is not exacerbated by additional prefrontal and striatal lesions in one hemisphere. Conversely, the animals are significantly more impaired after crossed prefrontal and striatal lesions of similar total magnitude. The results demonstrate than an intact cortico-striatal pathway is necessary to sustain performance on a classical prefrontal task, and provide a model within which to assess circuit reconstruction with novel cell therapies for brain repair.