Using a cross-sectional sample of 8th, 10th, and 12th grade Native American public school children, this study examines hypotheses pertaining to the ability and influence of measures drawn from social bonding, social learning, and social disorganization theories to account for variations in self-reported lifetime and 30 day use of alcohol, marijuana, and illicit drugs. Results derived from ordinary least squares regression equations show significant associations, most notably with variables from the social learning tradition. In addition, comparisons across equations show significant differences in the impact of the theoretical indicators on substance use between respondents in the sub-samples of those residing on and off reservations. The findings suggest that existing theories offer a promising framework for understanding the process of Native American substance use, and that the role of these in some cases differ for adolescents who reside on and off reservations. Contributions to the literature along with suggestions for future research are discussed.