Substance abuse has had profoundly devastating effects on the health and well-being of American Indians and Alaska Natives. A wide variety of intervention methods has been used to prevent or stem the development of alcohol and drug problems in Indian youth, but there is little empirical research evaluating these efforts. This article is an overview of the published literature on substance use prevention among Indian adolescents, providing background epidemiological information, a review of programs developed specifically for Indian adolescents, and recommendations for the most promising prevention strategies currently in practice.