ABSTRACT. Objective: This study examined racial/ethnic differences in alcohol, cigarette, and marijuana use among a diverse sample of approximately 5,500 seventh and eighth graders. We also evaluated the extent to which individual, family, and school factors mediated racial/ ethnic disparities in use. Method: Students (49% male) from 16 participating middle schools in southern California reported on lifetime and past-month substance use, individual factors (expectancies and resistance self-effi cacy), family factors (familism, parental respect, and adult and older sibling use), and school factors (school-grade use and perceived peer use). We used generalized estimating equations to examine the odds of consumption for each racial/ethnic group adjusting for sex, grade, and family structure. Path analysis models tested mediation of racial/ethnic differences through individual, family, and school factors. Results: After adjusting for sex, grade, and family structure, Hispanics reported higher and Asians reported lower lifetime and past-month substance use, compared with non-Hispanic Caucasians. Rates of substance use did not differ between non-Hispanic African Americans and Caucasians. Several individual factors mediated the relationship between Hispanic ethnicity and substance use, including negative expectancies and resistance selfeffi cacy. Higher use among Hispanics was generally not explained by family or school factors. By contrast, several factors mediated the relationship between Asian race and lower alcohol use, including individual, family (parental respect, adult and older sibling use), and school (perceived peer use, school-grade use) factors. Conclusions: Results highlight the importance of targeting specifi c individual, family, and school factors in tailored intervention efforts to reduce substance use among young minority adolescents. (J. Stud. Alcohol Drugs, 71, 640-651, 2010)