Underrepresentation among clinical trial participants contributes to evident health disparities and increasing diversity in clinical research is mutually beneficial to patients, providers, and researchers. Clinical trials offers participants critical treatment options, among other benefits, and vast opportunities are found in research-naïve populations. While reasons for this evident disparity in drug development have been documented, sustainable solutions have yet to be implemented. Several initiatives to increase diversity have been introduced by various stakeholders in pharmaceutical research—including changes in regulatory recommendations, engaging different investigators, and innovative partnerships. We developed a long-standing community-academic partnership with an Indigenous population in Montana—the Confederated Salish and Kootenai Tribes—who have largely been underrepresented in research. Our framework has overcome significant barriers and concerns regarding participation in research and can be translated to other overlooked populations. Concerted efforts to support research with diverse populations are required to reduce health inequities and optimize patient care.