American Indians and Alaska Natives (AI/ANs) endure some of the worst health disparities in the nation. The history of marginalization and exclusion of Indigenous voices from setting the research agenda, determining priorities, and conducting research will be explored. We will also define American Indian, Alaska Native, Native American, and Indigenous populations in the US; and we will describe the impact of preventable conditions on Indigenous health equity. We will also explore and identify opportunities to promote prevention science, methods, and implementation in AI/AN populations to improve outcomes.