Compulsive nicotine use is thought to be maintained by the acute reinforcing effects of nicotine and the reinforcement-enhancing effects of nicotine, in addition to the negative consequences of nicotine abstinence. Nicotine self-administration and nicotine-induced enhancement of non-nicotine reinforcers such as intracranial self-stimulation provide measures of these dual rewarding properties of nicotine. First, pharmacological manipulations that modulate the reinforcing and reinforcement-enhancing effects of nicotine are identified and discussed. Second, the interpretation and implications of data that identified shared and specific pharmacological substrates underlying the dual rewarding effects of nicotine are discussed, including implications for the preclinical testing of putative antismoking medications. In conclusion, reinforcement-related behaviors that are mediated by central reinforcement processes are likely to, and generally do, exhibit a number of common pharmacological substrates. Interestingly, however, a few pharmacological classes of compounds seem to exert selective effects on components of the dual nicotine reward mechanisms, indicating differences in the pharmacological substrates of the reinforcing and reinforcement-enhancing effects of nicotine. Further characterization of such compounds may ultimately lead to the identification of novel medications for nicotine dependence in humans.