PROJECT SUMMARY/ABSTRACT Alcohol and other drug use inequities have had devastating impacts for many American Indian/First Nations (Indigenous) communities and families. Social Determinants of Health (SDH) are critical mechanisms of risk and resilience for substance abuse (SA), substance use disorders (SUD), and recovery from SUD. This project will move beyond “risk-factor” epidemiology that largely ignores heterogeneity of SU patterns and impacts of SDH and has failed to materialize into substantial changes in population health outcomes. We will focus on identifying what matters most and to whom by examining relative impacts of SDH for SA over the life-course and across generations of Indigenous families. This competitive renewal application builds on our existing community-based participatory research with 8 tribal communities. We propose to continue computer-assisted survey interviews with existing Healing Pathways “target participants” (baseline N = 735) for whom we already have 11 waves of developmental data spanning childhood and early adulthood. We will enroll their own children in the study for multiple generations of epidemiological information on SA, SUD, recovery and resilience. We will also collect qualitative information to capture nuanced community perspectives on the contexts and mechanisms of substance use. Results of this research will increase awareness of the nature, etiology, and consequences of alcohol and other drug use problems and recovery in Indigenous reservation/reserve communities. Another outcome is enhanced precision in identifying SDH related to substance use and positive Indigenous development. Thus, the results of this project have potential to optimize the timing of and targets of intervention and prevention programs and policies in Indigenous communities.