The National Institutes of Health's guidelines for recruiting ethnic minorities and women into clinical research have raised numerous questions among investigators. Highlighted in this article are a number of important issues for those researchers seeking to include American Indians and Alaska Natives in their studies; that is, defining the population of American Indians and Alaska Natives for inclusion in a study, participation of the tribes in research and approval by the Institutional Review Board, issues of confidentiality and anonymity of individuals and tribes, identifying potential benefits to American Indian and Alaska Native communities, and the importance of evaluating the scientific merit of a proposed study. Awareness and a commitment to ongoing education regarding these issues will enhance the quality and benefits of research among American Indian and Alaska Native people.