Adverse life events are associated with a wide range of psychopathology, including an increased risk for substance abuse. In this review, we focus on the inter-relationship between exposure to adversity and brain development, and relate this to enhanced windows of vulnerability. This review encompasses clinical and preclinical data, drawing evidence from epidemiological studies, morphometric and functional imaging studies, and molecular biology and genetics. The interaction of exposure during a sensitive period and maturational events produces a cascade that leads to the initiation of substance use at younger ages, and increases the likelihood of addiction by adolescence or early adulthood. A stress-incubation/corticolimbic dysfunction model is proposed based on the interplay of stress exposure, development stage, and neuromaturational events that may explain the seeking of specific classes of drugs later in life. Three main factors contribute to this age-based progression of increased drug use: (1) a sensitized stress response system; (2) sensitive periods of vulnerability; and (3) maturational processes during adolescence. Together, these factors may explain why exposure to early adversity increases risk to abuse substances during adolescence.