OBJECTIVES: To review the epidemiology, research, and prevention programs for sexually transmitted diseases in American Indians and Alaska Natives (AI/ANs). STUDY DESIGN: We reviewed the current national and regional trends in sexually transmitted diseases (STDs) for AI/ANs from 1998-2004, peer-reviewed studies from January 1996, through May 2006, and reports, unpublished documents, and electronic resources addressing AI/AN STD prevention and control. RESULTS: STD prevalence among AI/ANs remains high. For example, the case rate of C. trachomatis in the North Central Plains AI/AN populations is 6 times the overall US rate. Trends for C. trachomatis also show sustained increases. Little research exists on STDs for this population, and most is focused on HIV/AIDS. Fear of compromised confidentiality, cultural taboos, and complex financial and service relationships inhibit effective surveillance, prevention, and management. CONCLUSIONS: Recommendations for STD control in this population include improved local surveillance and incorporation of existing frameworks of health and healing into prevention and intervention efforts. Research defining the parameters of cultural context and social epidemiology of STDs is necessary. © Copyright 2007 American Sexually Transmitted Diseases Association.