The proximal and distal effects of adversity on the onset of symptoms of substance dependence during adolescence were explored in two culturally distinct American Indian (AI) reservation communities (Northern Plains and Southwest). Data (N=3084) were from the American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP). The age-related risk of symptom onset increased gradually from age 11 through age 16, remained relatively high through age 18, then declined rapidly. Both tribe and gender were related to onset of dependence symptoms; men and Northern Plains tribal members were at greatest risk and Southwest women were at particularly low risk of symptom onset across adolescence. For all tribe and gender groups, both proximal and cumulative distal experiences of adversity were associated with substantially increased risk of symptom onset. The relationship of adversity to onset of substance dependence symptoms remained strong when previous symptoms of psychiatric disorder and childhood conduct problems were considered. These findings suggest that efforts to help children and adolescents in AI communities develop constructive mechanisms for coping with adversity may be especially valuable in substance dependence prevention.