The adolescent period is a time when most substance use is initiated and also a time when neural alterations in frontal control and subcortical incentive systems are taking place. Evidence from cross-sectional studies is accumulating for an imbalance between subcortical, dopamine-related activation and prefrontal control, which has been proposed to underlie the impulsive, risky decision making associated with adolescence. Adult substance abusers have alterations in this circuitry, but it remains unclear whether these alterations reflect pre-existing traits predisposing to substance use or are secondary to substance exposure. The talk will focus on research that probes the neural systems hypothesized to underlie the development of risk for substance use disorders. Findings from the Michigan Longitudinal Study, a prospective high-risk family study, will be presented, and the nationwide Adolescent Brain Cognitive Development study will be discussed.