Agnew's general strain theory (1985, 1989, 1992) has been tested several times since its development in the last decade. This theory, however, has seldom been applied to minority groups, such as American Indian population. Using a sample of 212 American Indian 5th to 8th grade adolescents, this analysis tests general strain theory by tracing the linkage among the measures of perceived discrimination, negative life events, family conflict, anger and internalization, and early onset of substance abuse. Mediating effects of anger and internalization were investigated using structural equation models. In addition, the strength of the stressor-substance abuse relationship was examined across groups with different levels of personal/social resources. High prevalence of substance abuse and life stressors, such as negative life events and perceived discrimination were found among these American Indian adolescents. Multiple indicators of life stressors were found to have positive effects on early onset of substance abuse directly and indirectly through self-reported anger. Specifically, effects of inconsistent parenting on adolescents' substance abuse were completely mediated through reports of anger. Negative life events directly affected substance abuse and had indirect effects on substance abuse through anger. Perceived discrimination led to negative affects such as internalization symptoms, but did not have significant effects on substance abuse. This study confirmed the mediating role of anger linking stressors and substance abuse; however, no mediating role of internalization was found. Furthermore, there was evidence that the strength of the anger-substance abuse relationship varied across groups with different levels of social/personal resources. With increasing levels of anger, adolescents with high self-esteem, negative attitudes toward deviance, and low levels of association with deviant peers were less likely to engage in substance abuse, compared with those with low level of self-esteem, positive attitudes toward deviance, and high levels of association with deviant peers. The relationship of life stressors and negative emotion (anger and internalization) was not moderated by social and personal resource variables. This study provided strong support to general strain theory and broadened its empirical generality to American Indian adolescents.