Historians and scholars from various disciplines have documented the pervasive influence of racism on American society and culture, including effects on the health and well-being of American Indian (AI) people. Among the many health problems affected by racial discrimination and oppression, both historical and current, are substance use disorders. Epidemiological studies have documented greater drug and alcohol-related morbidity and mortality among AI/ANs compared to other ethnic groups, and culturally appropriate, effective interventions are sorely needed. As part of a larger community based participatory research project to address substance use disparities in rural AI communities, we collected qualitative interview data from 25 AI key informants from a frontier reservation in Montana. Using a semi-structured interview guide, we asked participants to discuss their perceptions of the causes of substance use problems and barriers to recovery on the reservation. Although no questions specifically asked about discrimination, key informants identified stress from racism as an important precipitant of substance use and barrier to recovery. As one participant stated: “Oppression is the overarching umbrella for all sickness with drugs and alcohol.” Participants also identified historical trauma resulting from colonization as a manifestation of race-based stress that drives behavioral health problems. Findings suggest that interventions for AIs with substance use disorders, and possibly other chronic health problems, may be more effective if they address social determinants of health such as racial discrimination and historical trauma.