Purpose: The present study utilized Bronfenbrenner's social ecological theory (1979) to examine how family relations and religiosity mediate the relationship between environmental problems and adolescent substance abuse or dependence symptoms. Methods: A stratified random sample of 205 reservation and 196 urban American Indian adolescents living in a Southwestern area was interviewed in 2001. We measured substance abuse/dependence (using the DIS), risk factors (e.g., the familial problems of family members with addictions and child abuse, and the social problems of negative school environment and misbehaving peers) and meditating protective factors (family satisfaction and religious affiliation). Results: 27% of the sample met criteria for lifetime substance abuse or dependence (31% for reservation youth vs. 23% for urban youth). A structural equation model delineated the interrelations between family problems, social problems, religious affiliation, family satisfaction, and adolescent drug abuse/dependence symptoms. The retained final model fit the data very well (Chi-Square=7.4, p=.28, RMSEA=.03 with 90% Upper Confidence Limit=.08, CFI=.99, NNFI=.99). 40% of the variance in substance symptoms was determined by addicted family members (beta=.14), misbehaving peers (beta=.56), and family satisfaction (beta= –.11). Negative school environment, child abuse experience and religiosity had no direct effect on substance symptoms, but did help determine family satisfaction. 17% of the variance in family satisfaction was determined by religious affiliation (beta=.10), addicted family members (beta=–.19), child abuse (beta=–.25), and negative school environment (beta=–.14). In addition, 2% of religious affiliation was determined by school environment (beta=.12) and misbehaving peers (beta=–.11). Implications for Practices: The results indicate that family satisfaction influences adolescent substance symptoms, mediating the direct effects of family members with addictions, child abuse experience and school problems. Although religious affiliation did not mediate between environmental problems and such symptoms, it mediated social problems and family satisfaction. Intervention and prevention efforts may benefit from promoting family satisfaction to reduce adolescent substance problems(Funded by NIDA Grant # 1 RO1 DA13227-01).