Adolescence is a developmental period during which youth are at increased risk for using substances. An empirical focus on core competencies illustrates that youth are less likely to use substances when they have a positive future orientation, a belief in the ability to resist substances, emotional and behavioral control, sound decision-making ability, a belief that substance use is wrong, and a strong bond to prosocial peers and family. Such etiological research is beginning to provide a strong foundation for successful competence-building prevention programs. Focusing on the developmental-ecological context of adolescent substance use will expedite advances in prevention.