The authors test biosocial models that posit interactions between biological variables (testosterone, estradiol, pubertal status, and pubertal timing) and social context variables (family, peer, school, and neighborhood) in predicting adolescent involvement with cigarettes and alcohol in a sample of 409 adolescents in Grades 6 and 8. Models including the biological and contextual variables and their interactions explain significantly more variance in adolescent cigarette and alcohol involvement than do models including only the main effects of the biological and contextual variables. Post hoc analyses of significant interactions suggest that, in most cases, moderation occurred in the hypothesized direction. Consistent with dual hazards models of adolescent antisocial behaviors, the relationships between the biological and substance use variables become positive and stronger as the context becomes more harmful. Considerations of adolescent substance use should recognize the possible role of biological variables and how their influence may vary by social context. (Contains 3 tables.)