The progression of substance use and the patterns of comorbidity of substance use and psychiatric disorders are explored prospectively in young adolescents enrolled in the Great Smoky Mountains Study. This study is an epidemiologic study of white and American Indian youths living in rural Southern Appalachia. Results from this study indicate that alcohol use without permission predicts subsequent use of illicit drugs and regular tobacco use. Use of tobacco was not associated with either later alcohol or drug use. Patterns of comorbidity showed strong cross-sectional relationships between substance use and behavioral disorders, but not emotional disorders. Use of alcohol was also associated with psychiatric diagnosis at a later interview. There were some differences between white and American Indian youths in the pattern of comorbidity of tobacco use and psychiatric disorder and the relationship between prior psychiatric disorder and later alcohol use. These findings suggest that alcohol use without permission may be an important marker for youths who are at risk for illicit drug use and/or psychiatric diagnoses.