The mediodorsal nuclei of thalamus (MD), prefrontal cortex (PFC), and nucleus accumbens core (NAc) form an interconnected network that may work together to subserve certain forms of behavioral flexibility. The present study investigated the functional interactions between these regions during performance of a cross-maze-based strategy set-shifting task. In Experiment 1, reversible bilateral inactivation of the MD via infusions of bupivacaine did not impair simple discrimination learning, but did disrupt shifting from response to visual cue discrimination strategy, and vice versa. This impairment was due to an increase in perseverative errors. In Experiment 2, asymmetrical disconnection inactivations of the MD on one side of the brain and PFC on the other also caused a perseverative deficit when rats were required to shift from a response to a visual cue discrimination strategy, as did disconnections between the PFC and the NAc. However, inactivation of the MD on one side of the brain and the NAc contralaterally resulted in a selective increase in never-reinforced errors, suggesting this pathway is important for eliminating inappropriate strategies during set shifting. These data indicate that set shifting is mediated by a distributed neural circuit, with separate neural pathways contributing dissociable components to this type of behavioral flexibility.