Drug addiction is presented as a cycle of spiraling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and loss of control over drug use. Sensitization and counteradaptation are hypothesized to contribute to this hedonic homeostatic dysregulation. Neurobiological mechanisms involved, such as the mesolimbic dopamine system, opioid peptidergic systems, and brain and hormonal stress systems, are beginning to be characterized. This framework provides a realistic approach to identifying neurobiological factors that produce vulnerability to drug addiction and to relapse in individuals who have a history of drug addiction. Implications of the framework for the concept of drug addiction and for drug treatment are discussed. 51 references and 4 figures