Early onset substance use has consistently been associated with increased risk for a range of adverse outcomes in late adolescence and early adulthood. However, the mechanisms that underlie this relationship are not fully understood. Recent advances in developmental neuro-science, together with emerging literature on early onset substance use, suggest that the adolescent brain may be more vulnerable to the effects of addictive substances because of the extensive neuromaturational processes that are occurring during this period. Such findings are suggestive of disrupted developmental trajectories in early onset users, although there is growing evidence that high-risk youths have premorbid neurobiological vulnerabilities. Prospective studies investigating neurobiological correlates and sequelae of early adolescent drug use are urgently required to inform appropriate public health responses.