American Indian and Alaska Native (AI/AN) cultures in the United States include a diverse group of indigenous cultures that have been affected by their contact with European Americans and have suffered adverse psychological, physical, and economic consequences. AI/AN adolescents have the highest prevalence of cigarette smoking of all U.S. ethnic groups. Culturally competent health promotion programs are needed to enhance their resiliency and help them avoid recreational, addictive use of commercial tobacco. The authors describe the diverse AI/AN populations and their unique health and social issues, including adolescent smoking. They present examples of smoking prevention programs tailored or adapted for AI/AN adolescents and make recommendations for implementation and evaluation of prototype programs. Recommendations include involving the community, respecting tribes' wishes for confidentiality, being aware of IRB issues, beginning with formative and qualitative research, using culturally appropriate measures, understanding the diversity of AI/AN cultures, and involving multiple generations of the family.