In 1990, researchers and health care professionals joined with members of several southwestern Native American communities to form an HIV/AIDS and substance abuse prevention partnership. Culturally sensitive approaches to theory-based interventions were developed into highly replicable, structured, school-based and community-based intervention programs. Process evaluations indicated high levels of program acceptance and fidelity. Outcome evaluations demonstrated significant positive preventive intervention effects among participants. This article reports how NAPPASA school prevention curricula were developed and discusses three critical processes in developing these successful curricula: 1) selection of integrative theory to address the multi-dimensional antecedents of HIV/AIDS and substance abuse among Native Americans, 2) use of ethnographic methodology to obtain intensive input from target groups and community members to ensure cultural and developmental sensitivity in the curriculum, and 3) use of process and outcome evaluations of pilot and field trials to develop an optimal curriculum.