Abstract The diversification of genomics research cohorts is a national priority intended to accelerate research and improve individualized prevention, treatment and care. Concrete, tailored strategies are needed to ethically engage various underrepresented populations to promote equitable access to genomic discovery and translation. One region of the U.S. in which such strategies are likely to be of particular importance is the rural South. U.S. residents in the rural South experience persistent health disparities; have limited knowledge about genetics and genomic science; are underrepresented in genomics research; and would likely benefit substantially from scientific advances in genomics. Importantly, the structurally embedded factors that hinder members of rural communities from accessing advances in health care—and ultimately perpetuate health inequities—might similarly impair widespread, informed, participation in genomics. However, the ethical, legal, and social implications (ELSI) of conducting genomics research with residents in the rural South are not well-understood. As such, there is a critical need to engage rural populations in the full spectrum of genomics research to establish ethical frameworks and guidelines that reflect their unique values, preferences and priorities. The proposed study employs stakeholder-engagement methods with consideration to the ethical, legal, social and cultural contexts relevant to the lived experiences of individuals living in the rural South to inform evidence-based guidelines that facilitate effective translation of genomics research and discovery. This study consists of three phases, employing a sequential qualitative research design engaging multiple stakeholders, including local community members, potential study participants, and content experts throughout the research process to integrate diverse perspectives. Drawing from the social, behavioral, and biological sciences, this study has the potential to serve as a model to guide genomics research for other medically underrepresented populations to ultimately identify best practices for community translation of genomic discoveries.