There are few substance use treatment and prevention programs for AI/AN people that integrate culturally based practices with evidence-based treatment and prevention. The National Institutes of Health’s (NIH’s) Helping to End Addiction Long-term (HEAL) Prevention Cooperative supports two projects focused on AI/AN populations. One focuses on youth ages 15 to 20 years living within the Cherokee Nation reservation, a multicultural rural area in northeastern Oklahoma, and the second focuses on emerging adults ages 18 to 25 years living in diverse urban areas. We provide a brief overview of the two prevention trials and a case comparison across approaches using the framework of promising practices for intervention science with Indigenous communities (Whitesell et al., 2020) related to (1) integration of Indigenous and academic perspectives to respond to community needs, (2) community partnership and engagement, (3) alignment with Indigenous cultural values and practices, (4) capacity building and empowerment, (5) implementation within complex cultural contexts, and (6) tribal oversight. Overall, these two projects highlight the importance of long-standing relationships with community partners, engaging the community at all levels to ensure that programming is culturally and developmentally appropriate, and having tribal and elder oversight. These practices are key to establishing trust and building confidence in research in these communities and ensuring that research can benefit AI/AN people. These studies showcase how strong partnerships can advance health and support the conduct of rigorous science to help pinpoint optimal health solutions by identifying efficacious, culturally grounded intervention strategies. Although the sovereign status of tribes demands this type of partnership, this research serves as a model for all community research that has a goal of improving health.