Current social developmental theories of drug use often incorporate mediation processes, but it is generally unknown whether these mediation processes generalize across ethnicity and gender. In the present study, we developed a mediation model of substance use based on current theory and research and then tested the extent to which the model was moderated by gender and ethnicity (African American, European American, and Hispanic American), separately for 8th and 10th graders. The respondents were adolescents from the 1994, 1995, and 1996 cohorts of the Monitoring the Future (MTF) project, which conducts yearly in-school surveys with nationally representative samples. Multi-group, structural equation modeling (SEM) results indicated much similarity across gender and ethnicity for school success and time spent with friends as partial mediators of risk taking and parental involvement on drug use (controlling for parental education). However, there were some differences in the magnitude of indirect effects of parental involvement and risk taking on substance use for 8th-grade African American girls. Discussion focuses on the potential success of prevention efforts across different ethnicities and gender that target parent-child relationship improvement and risk taking, and considers possible culture- and gender-specific issues.