Despite concerns surrounding the possible adverse effects of marijuana on complex cognitive function, the processes contributing to the observed cognitive deficits are unclear, as are the causal relationships between these impairments and marijuana exposure. In particular, marijuana-related deficits in cognitive flexibility may affect the social functioning of the individual and may contribute to continued marijuana use. We therefore examined the ability of rats to perform affective and attentional shifts following acute administration of Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive marijuana constituent. Administration of 1 mg/kg THC produced marked impairments in the ability to reverse previously relevant associations between stimulus features and reward presentation, while the ability to transfer attentional set between dimensional stimulus properties was unaffected. Concurrent in situ hybridization analysis of regional c-fos and ngfi-b expression highlighted areas of the prefrontal cortex and striatum that were recruited in response to both THC administration and task performance. Furthermore, the alterations in mRNA expression in the orbitofrontal cortex and striatum were associated with the ability to perform the reversal discriminations. These findings suggest that marijuana use may produce inelasticity in updating affective associations between stimuli and reinforcement value, and that this effect may arise through dysregulation of orbitofrontal and striatal circuitry.