Background: American Indians and Alaska Natives (AI/ANs) have some of the highest rates of substance use compared with other ethnic groups. Native American youth start experimenting with drugs at younger ages, continue to use them after initial experimentation, and thus seem to mirror the same drug use patterns as their older peers. Despite the seriousness of the problem, there is a lack of evidence-based drug prevention interventions for AI/AN youth. Objectives: This review article describes the process by which an existing evidence-based, culturally relevant drug prevention intervention was transformed into a low-cost, computerized intervention digitized in order to extend its reach to Native American youth in reservations and rural locations. Methods: The intervention, titled HAWK2 (Honoring Ancient Wisdom and Knowledge2: Prevention and Cessation) is aimed at young Native children in elementary school settings (grades 4 and 5) and uses engaging multimedia features such as games, animations, and video clips to impart substance abuse prevention knowledge and skills training. The development of this intervention was a collaborative process involving the participation of community experts, research scientists, school teachers, and practitioners, as well as Native youth. Specific examples are provided to illustrate the development processes. Results: Initial feedback from practitioners and youth suggest the feasibility and acceptability of computer-based interventions by Native youth and practitioners. Scientific Significance: Computer-based interventions are a cost-effective way of engaging youth in prevention programming. Future studies of HAWK2 will provide an important means of testing the long-term effectiveness of self-administered, computer-based interventions for AI/AN youth.