Alcohol is the most commonly used and abused substance among adolescents in the United States. Its abuse, in particular among Native American adolescents, has led to the highest incidence of Fetal Alcohol Syndrome in the nation. While absolutely preventable, FAS prevention efforts to date have been minimally successful in reducing its incidence. This multi-phased project surveyed prevention specialists and gatekeepers in major prevention programs in six states with large Indian populations and designed and evaluated a viable prevention strategy that targets Native American adolescents at highest risk of engaging in behaviors that lead to FAS births. The study indicated that a community-based prevention program targeting 6th through 8th grade students has the highest probability of success. Specific strategies, including types of communication media, materials and tools acceptable to the target population, as well as the role of parents, extended family, peers, and culture are discussed in some detail.