American Indian youth have been shown to be at high risk for drug abuse. Epidemiological studies of Indian school students over the past two decades have revealed rates of use consistently higher than those found for other youth. Socioeconomic and historical factors have led to conditions that put a great deal of stress on the family and other support systems which in part account for the seriousness of the problem. A model is presented which can guide both prevention and treatment efforts addressing drug abuse in Indian communities. Five variable domains, social structure, socialization factors, psychological variables, peer associations and drug use, are related in an integrated structure. By following the progression of the etiological variables, a stepwise plan can be developed to organize interventions. Although the model has immediate utility, a number of further research questions are outlined that will enhance its application.