The purpose of this article is to explore the historical issues that affect research in American Indian communities and examine the implications of these issues as they relate to culturally sensitive, respectful, and appropriate research with this population. Methods include review and analysis of the literature and examination of our collective experience and that of our colleagues. Recommendations are given for conducting culturally sensitive, participatory research. We conclude that research efforts must build on the establishment of partnerships between investigators and American Indian communities to ensure accurate findings and analyses and to implement culturally relevant benefits.