Drugs of abuse are able to elicit compulsive drug-seeking behaviors upon repeated administration, which ultimately leads to the phenomenon of addiction. Evidence indicates that the susceptibility to develop addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. Addiction is hypothesized to be a cycle of progressive dysregulation of the brain reward system that results in the compulsive use and loss of control over drug taking and the initiation of behaviors associated with drug seeking. The view that addiction represents a pathological state of reward provides an approach to identifying the factors that contribute to vulnerability, addiction, and relapse in genetic animal models.