Institutional review boards (IRBs) function to regulate research for the protection of human participants. We share lessons learned from the development of an intertribal IRB in the Rocky Mountain/Great Plains Tribal region of the United States. We describe the process through which a consortium of Tribes collaboratively developed an intertribal board to promote community-level protection and participation in the research process. In addition, we examine the challenges of research regulation from a Tribal perspective and explore the future of Tribally regulated research that honors indigenous knowledge and promotes community accountability and transparency. We offer recommendations for researchers, funding agencies, and Tribal communities to consider in the review and regulation of research.