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OBJECTIVE: This study examines differences in adolescents' use of tobacco, alcohol, and illicit drugs by racial and ethnic groups. METHODS: The authors analyzed questionnaire data from large, nationally representative samples of U.S. high school seniors to examine differences in drug use prevalence and trends among racial and ethnic groups between 1976 and 2000. RESULTS: On average, American Indian seniors showed the highest levels of tobacco, alcohol, and illicit drug use. Cuban American and white seniors also tended to have relatively high levels of substance use, followed by Mexican American and Puerto Rican seniors. Other Latin American, African American, and Asian American seniors reported the lowest levels of drug use. Most of these differences are longstanding, but some have widened and others narrowed during the past 25 years. CONCLUSION: Significant differences exist in adolescent use of tobacco, alcohol, and illicit drugs by racial and ethnic groups, and these differences have changed over time. Future research should examine these differences and seek to identify the sources and consequences of the disparities.