Purpose-The purpose of this chapter is to provide a comprehensive overview of the substance use disparities among American Indian/Alaska Native (AI/AN) youth, the contributing factors to these disparities, proven and promising approaches through strengths-based methods, barriers to implementation of prevention and treatment efforts, and future recommendations for effective programs and research. Approach-We have conducted a thorough literature review of relevant research studies, as well as a review of government, tribal, and community-based curricula and resources. This review of programs is not exhaustive but provides several examples of best practices in the field and suggestions for future directions. Social implications-We strongly advocate that to accurately explore the true etiology of substance abuse and to respond to the concerns that AI/ AN have prioritized, it is necessary to utilize a strengths-based approach and draw upon traditional AI/AN perspectives and values, and active community participation in the process. More specifically, prevention and treatment programs should use methods that incorporate elders or intergenerational approaches; foster individual and family skills-building; promote traditional healing methods to recognize and treat historical, cultural, and intergenerational and personal trauma; focus on early intervention; and tailor efforts to each Native nation or community. Value-Ultimately, to reduce substance abuse disparities in AI/AN youth, we must find better ways to merge traditional Native practices with western behavioral health to ensure cultural competency, as well as to develop mechanisms to effect system-and policy-level changes that reduce barriers to care and promote the well-being of AI/AN youth, families, and communities.