We examined frequency and intensity of racial/ethnic discrimination and the longitudinal relationship to substance use. The sample included (N = 1,421) American Indian, American Indian and White, and White adolescents. A high frequency of perceived racial discrimination was associated with an increased risk for heavy alcohol use, prescription drug misuse, and other illicit drug use. Experiences of perceived racial discrimination high in intensity were associated with further increased risk of prescription drug misuse and other illicit drug use. Race/ethnicity did not moderate the relationship between perceived racial discrimination and substance use. Interventions targeting the deleterious effects of racial discrimination may need to be designed to account for both the environment and the individual.