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This essay proposes six basic assumptions to guide the development of prevention research partnerships between Native American communities and non-Native American prevention researchers. It also presents a five-stage theoretical model for the development of culturally specific prevention research. The theoretical model addresses the need for: (a) the cultural translation of key prevention constructs pertaining to risk and protective factors and (b) the development of measures of culturally specific risk and protective factors that will contribute to explained variance over and above that explained by traditional European models. “Cultural translation” refers to the process of adapting key variables to reflect their expression in specific social contexts. “Culturally specific risk and protective factors” refers to risk and protective factors unique to a specific culture, such as the protective effects of traditional spirituality and traditional activities in Native American cultures. The essay concludes with short- and long-term goals for prevention research in Native American communities.