Research on the inter-relationship between drug abuse and social stress has primarily focused on the role of stress exposure during adulthood and more recently, adolescence. Adolescence is a time of heightened reward sensitivity, but it is also a time when earlier life experiences are expressed. Exposure to stress early in postnatal life is associated with an accelerated age of onset for drug use. Lifelong addiction is significantly greater if drug use is initiated during early adolescence. Understanding how developmental changes following stress exposure interact with sensitive periods to unfold over the course of maturation is integral to reducing their later impact on substance use. Arousal levels, gender/sex, inflammation, and the timing of stress exposure play a role in the vulnerability of these circuits. The current review focuses on how early postnatal stress impacts brain development during a sensitive period to increase externalizing and internalizing behaviors in adolescence that include social interactions (aggression; sexual activity), working memory impairment, and depression. How stress effects the developmental trajectories of brain circuits that are associated with addiction are discussed for both clinical and preclinical studies.