Despite the well-established finding that American Indian adolescents are at a greater risk of illicit substance use and abuse than the general population, few generalist explanations of deviance have been extended to American Indian substance use. Using a popular generalist explanation of deviance, General Strain Theory (GST), we explore the predictive utility of this model with a subsample of American Indian adolescents from Waves I and II of the National Longitudinal Study of Adolescent Health (Add-Health). Overall, we find mixed support for the utility of GST to account for American Indian adolescent substance use. While exposure to recent life events, a common measure of stress exposure, was found to be a robust indicator of substance use, we found mixed support for the thesis that negative affect plays a key role in mediating the link between strain and substance use. However, we did find evidence that personal and social resources serve to condition the link between stress exposure and substance use, with parental control, self-restraint, religiosity, and exposure to substance using peers each serving to moderate the association between strain and substance use, albeit in more complex ways than expected.