Health disparities exact a devastating toll upon Indigenous people in the USA. However, there has been scant research investment to develop strategies to address these inequities in Indigenous health. We present a case for increased health promotion, prevention, and treatment research with Indigenous populations, providing context to the recent NIH investment in the Intervention Research to Improve Native American Health (IRINAH) network. We discuss the disproportionate costs and consequences of disparities borne by Indigenous groups, the limited evidence base on effective intervention for this population, how population uniqueness often makes transfer of existing intervention models difficult, and additional challenges in creating interventions for Indigenous settings. Given the history of colonial disruption that has included genocide, forced removal from lands, damaging federal, state and local policies and practices, environmental contamination, and most recently, climate change, we conclude research that moves beyond minor transformations of existing majority population focused interventions, but instead truly respects Indigenous wisdom, knowledge, traditions, and aspirations is needed, and that investment in intervention science to address Indigenous health disparities represent a moral imperative.