One of the characteristic features of adolescence is a tendency to risky behaviors including experimentation with psychoactive substances. The current review covered empirical studies on the associations of Behavioral Approach System (BAS) and Behavioral Inhibition System (BIS) with adolescent substance use. The best predictors are the two components of BAS - reward responsiveness and fun seeking/impulsivity; the evidence on the role of BIS is contradictory. Recent neurological studies suggest that developmental differences in brain pathways underlying approach and avoidance motivation may be one mechanism through which adolescents are placed at greater risk for substance experimentation and misuse. Although adolescents as a group are considered risk-takers, some adolescents will be more prone than others to engage in risky behaviors, putting them at potentially greater risk for negative outcomes. These individual and developmental differences may help explain vulnerability in some individuals to risk-taking associated with substance use. Efforts to prevent or minimize adolescent risk-taking should focus on changing the context in which risky activity takes place.