PROJECT SUMMARY Drug and alcohol use related health problems and overdose deaths disproportionately impact quality and longevity of life for many American Indian and Alaska Native (Indigenous) communities. The proposed Community-Driven Indigenous Research, Cultural Strengths & Leadership to Advance Equity in Substance Use Outcomes (CIRCLE) Center of Excellence (P50) aims to address drug use related health problems in collaboration with diverse Indigenous communities. Through research, training, and outreach, we will respond to calls from Indigenous Peoples for enhanced focus on recovery and prevention, sources of strength, culture and family-based approaches to wellness, and policy solutions. The P50 projects and cores will operate with emphasis on four cross-cutting domains, all centered on a bedrock of promoting Indigenous Health Equity: 1) Indigenous & Allied Leadership; 2) Community/Tribally Based Participatory Research (C/TBPR); 3) Addressing Heterogeneity via Precision Public Health; and 4) Centering Strengths, including Assessing Indigenous Cultural Frameworks of Health. Reflecting these thematic approaches, the Center's overarching aims include conducting impact-focused, C/TBPR to identify heterogeneity in substance use risk and protective factors and intervention effects. We will also foster the development of Indigenous scholars to expand Indigenous autonomy, capacity and innovation in research, practice, and policy surrounding alcohol and drug use. We further aim to expand and deepen our engagement with educational facilities, researchers, Tribal and Urban Native communities, policy makers, and the public to serve as a national resource for more rapid uptake and sharing of novel methods, measures, and programs in service to Indigenous health equity. To achieve these goals, the Center will house the following: 1) Administrative Core to oversee governance, administrative structures, scientific priorities, and training activities; 2) Research Core to provide methodological expertise to support the research of the Center; 3) Pilot Project Core to support innovation in Indigenous drug use research, and 4) Three Research Projects that will conduct multidisciplinary and synergistic science focused on drug use prevention, intervention, and policy. The proposed work aligns with NIDA's Racial Equity Initiative action steps, including increased CBPR and equity- driven partnerships to combat drug use inequities.