Dopamine is critical for directing goal-oriented behavior. We investigated dopamine D2 receptor involvement in reversal learning and reinforcement efficacy in mice lacking functional dopamine D2 receptors and their heterozygous and wild-type littermates. Mice discriminated between two odors to receive a food reinforcer. One odor signaled a reinforcer (S+); the other odor signaled no reinforcer (S-). After mice learned the S+/S- relationship, we inverted the reinforcement contingencies. The necessary number of trials to relearn the new reinforcement contingencies served as our index of reversal learning. Mice lacking functional dopamine D2 receptors repeatedly failed to inhibit previously reinforced responses during reversal trials. In a separate experiment, mice responded for reinforcers on a progressive ratio schedule of reinforcement. Mice lacking functional dopamine D2 receptors earned significantly fewer reinforcers than did heterozygous mice. Our results suggest that dopamine D2 receptors regulate reversal learning and influence the reinforcing efficacy of natural rewards.