A conceptual structure for drug addiction focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework with which to identify the neurobiologic neuroadaptive mechanisms involved in the development of drug addiction. The brain reward system implicated in the development of addiction is comprised of key elements of a basal forebrain macrostructure termed the extended amygdala and its connections. Neuropharmacologic studies in animal models of addiction have provided evidence for the dysregulation of specific neurochemical mechanisms not only in specific brain reward circuits (opioid peptides, gamma-aminobutyric acid, glutamate and dopamine) but also recruitment of brain stress systems (corticotropin-releasing factor) that provide the negative motivational state that drives addiction, and also are localized in the extended amygdala. The changes in the reward and stress systems are hypothesized to maintain hedonic stability in an allostatic state, as opposed to a homeostatic state, and as such convey the vulnerability for development of dependence and relapse in addiction.