The subthalamic nucleus (STN) is part of the basal ganglia, which play a crucial role in motor control and in processing information from motor cortical areas. Although the STN is classically considered a motor structure, recent studies suggest that it may also be involved in the motivation for natural and drug reward. The STN may differentially modulate natural and drug reward via circuitry that includes the nucleus accumbens (NAcc), a structure belonging to the mesocorticolimbic circuit which has been identified as the neural substrate of the reinforcing effects of reward. Here, we assess the effects of bilateral STN lesions on the self-administration (SA) and subsequent reinstatement of sucrose- and cocaine-seeking behavior. Bilateral STN lesions block reinstatement of cocaine-seeking behavior, but not the reinstatement of food-seeking behavior. Neuronal correlates in the NAcc are also investigated. NAcc neurons respond to cocaine or sucrose and the conditioned stimulus (CS) during SA and the CS during reinstatement. Moreover, STN lesions have profound effects on these responses. Additionally, we assess the effects of STN lesions on operant responding for reward under a progressive ratio (PR) schedule of reinforcement, a schedule thought to measure the reinforcing efficacy of rewards. Bilateral STN lesions enhance responding for sucrose reward, but attenuate responding for cocaine reward. Furthermore, STN lesions differentially modulate NAcc neuronal activity associated with operant responding for either sucrose or cocaine reward under a PR schedule of reinforcement. Collectively, these results provide additional evidence for the role of the STN in food- and cocaine-seeking behavior and further support the NAcc in food- and cocaine-seeking behavior. In conclusion, these experiments demonstrate that the STN, classically considered a motor nucleus, differentially modulates the motivation, or craving, for natural and drug reward.