Tobacco smoking is the leading cause of preventable premature death in the developed world, and nicotine appears to be the main critical psychoactive component in establishing and maintaining tobacco dependence. Rewarding effects of nicotine, which underlie its abuse potential, can be modulated by manipulating the endocannabinoid system. For example, pharmacological blockade or genetic deletion of cannabinoid receptors, as well as the use of drugs that increase endocannabinoid levels, reduce or eliminate many behavioral and neurochemical effects of nicotine that are related to its addictive potential. This chapter focuses on the published literature on cannabinoid–nicotine interactions in nicotine addiction, highlighting the possibility that the endocannabinoid system may serve as a new target for the development of medications for the treatment of tobacco dependence.