PROJECT SUMMARY Decades of research has failed to address Indigenous drug and other substance use inequities in the United States. These persistent challenges call for new systems and methods to turn the tide on Indigenous substance use prevention, programs, and policies. The Research Core will serve as a central resource for methods support and analyses for CIRCLE's proposed research and evaluation projects designed to build resources and evidence for culture as a core source of healing and prevention of substance use morbidity and mortality disparities resulting from centuries of colonizer-based racial trauma and oppression. The Research Core is led by a team of Indigenous and allied leadership who will provide operational support in Indigenous research methodologies; community partnership and culturally responsive engagement; substance use epidemiology; longitudinal, quantitative, qualitative, and mixed-methods analyses; multilevel and mixture modeling; implementation science; and data management, sovereignty, and stewardship in line with CIRCLE's overall aims and objectives. In addition, the Research Core will advance four methods innovation projects designed to: (1) conceptualize and operationalize “culture” as a key construct for addressing problematic substance use within and across Indigenous communities and settings; (2) characterize novel outcomes and measurement approaches for concepts of pre-addiction and recovery in Indigenous populations; (3) enhance understanding of heterogeneity in interventions, implementation, and policies to inform precision approaches to substance use research with Indigenous communities; and (4) operationalize the Indigenist Ecological Systems Model through creation of a repository of measures and associated resources. The Research Core will also support innovative pilot work by early-career investigators from diverse disciplines and helps them develop pilot research into robust lines of extramurally funded research. Finally, the Research Core will support dissemination of the CIRCLE's methodological advances and research findings in collaboration with the Administrative Core.