Challenges in recruiting American Indians and Alaska Natives into cancer clinical trials are addressed in this article. Researchers, health care providers, and American Indian and Alaska Native patients face significant communication barriers when prevention or treatment trials are designed or implemented. For researchers, the challenges lie in understanding the cultural distinctiveness of individual tribes, coping with the family orientation of Indian subjects, dealing with the lack of standardized research measures, and defining the subject's pathway in seeking and obtaining healing and health care services. For providers, the challenges center on patient-provider communication, illness beliefs, transportation, and sociocultural barriers. This article explores these complex issues and offers recommendations for researchers and health care providers on conducting research in American Indian and Alaska Native populations.