Compulsive drug intake is a hallmark of addiction, yet a mechanistic understanding of this process has been elusive. Drug use is initiated primarily to obtain the excitatory actions of addictive drugs on brain reward systems. Paradoxically, excessive drug intake can decrease the activity of reward systems, reflected in elevated intracranial self-stimulation thresholds in rats, probably by engaging compensatory mechanisms to counter drug effects. Recent evidence suggests that compulsive drug intake might develop in response to such adaptive decreases in brain reward systems. Further, the actions of addictive drugs on reward systems are susceptible to classical conditioning processes, providing a potential mechanism by which drug-paired stimuli can induce powerful cravings and precipitate relapse in abstinent drug users. These findings provide a conceptual framework for improving our understanding of compulsive drug use, and might facilitate the development of novel therapeutics for substance abuse disorders.