ABSTRACT American Indian and Alaska Native (Al/AN) populations have the highest opioid overdose related death rate in the United States, and the rate continues to rise. At the same time, access to prevention, treatment, and recovery services is limited to some Indian Health Service (IHS) and Tribal health facilities, where provider shortages, confidentiality concerns, lack of culturally centered services, mistrust of clinicians, and insufficient fiscal resources are commonplace. AI/ANs also face unique social and structural conditions which intersect with substance use and perpetuate the aforementioned disparities including colonialism and racism, historical and intergenerational trauma, poverty, unemployment, mental health concerns, etc. The Native Collective Research Effort to Enhance Wellness (N CREW) Program proposed by the Albuquerque Area Indian Health Board, Inc. (AAIHB), and its Albuquerque Area Southwest Tribal Epidemiology Center (AASTEC), therefore aims to plan, develop, and implement community-led research, research capacity enhancement, and data improvements, to respond to the opioid/drug public health emergency within our 27-Tribe service area spanning across New Mexico, Colorado, Texas and Utah. Our overall goal is to build and strengthen the research capacity within our tribal organization and the tribes we serve to generate knowledge and improve outcomes related to overdose, substance use, and related factors including mental wellbeing. Specific aims that we will pursue to achieve our overall goal during this initial two-year program phase, center upon development and planning activities, including: 1) cultivate research partnerships and elucidate community-prioritized research topics for future implementation by AAIHB/AASTEC and its member tribes; 2) enhance capacity within our Tribal Organization/Tribal Epidemiology Center, and the 27 member tribes in our service area, to conduct locally prioritized research related to overdose, substance use, and related factors; and 3) improve access to and the quality of Al/AN data on substance use and related health and wellbeing factors to maximize their potential for use in local decision-making. Our primary hypothesis is that strengthening research capacity within a tribal organization and its member tribes, and focusing studies on tribally prioritized topics led by Native researchers and allies, will elucidate culturally grounded, strengths-based, effective and sustainable intervention strategies that support substance use prevention, treatment, and recovery.