This special issue on Promoting Health Equity through Rigorous, Culturally Informed Intervention Science: Innovations with Indigenous Populations in the United States is a welcome addition to the growing recognition that culture is fundamental to effective intervention design, implementation, and research, in this instance among Indigenous peoples of North America and the Pacific. The articles herein summarize some of the priorities, findings, and lessons learned through work conducted by researchers in the National Institutes of Health Intervention Research to Improve Native American Health (IRINAH) consortium. The lessons learned encourage rethinking of the epistemological imperatives of our science; recognizing the rich, important variation in the lived experience of Indigenous peoples; and a greater appreciation for the critical role this experience plays in conceptualizing, designing, and operationalizing effective interventions. In this regard, the authors return us to a nearly 3 decades' old, but largely unrealized commitment by the National Institutes of Health to the thoughtful inclusion of underrepresented racial and ethnic minorities in its sponsored research as a means of improving the clinical and implementation sciences. The findings summarized in this special issue demonstrate the value of such efforts and fit well within existing paradigms that emphasize the importance of culture for maximizing the relevance and impact of this work. Yet the remaining challenge is to promote this agenda in ways that invite others to contribute in equally deliberate and informed ways, and thereby advance the field at large.