Research on the prevention of substance abuse among American Indian and Alaska Native youth offers challenges and demands careful methods. This paper describes such challenges in terms of philosophical, political, and cultural issues surrounding substance abuse prevention research with American Indian and Alaska Native people. The authors suggest how social work researchers can address these issues through strategies of community collaboration, goal setting, and cultural sensitivity. The paper discusses the limits, implications, and future applications of the described strategies for research on the prevention of alcohol and drug abuse among American Indian and Alaska Native youth.