In comparison with the general population, research indicates a need for greater health equity among American Indian and Alaska Natives (AI/AN). AI/ANs have demonstrated remarkable resilience in response to centuries of historical oppression, yet growing evidence documents mental health disparities. Consequently, some AI/AN youth, defined as 18 years or younger, experience elevated rates of suicide, substance use disorders, conduct and oppositional defiant disorders, attention deficit-hyperactivity disorders, and posttraumatic stress disorders. In this chapter, we systematically review the growing body of research examining the culturally specific risk and protective factors related to AI/AN youth wellness. This review includes published, peer-reviewed qualitative and quantitative research on AI/AN youth between the years 1988 to 2013. Organizing risk and protective factors within an ecosystemic resilience framework, the following broad risk and protective factors are critically reviewed: societal factors (historical oppression and discrimination), cultural factors (ethnic identity, spirituality, and connectedness), community factors (community environment, school environment, peer influence, and social support), family factors (family support, family income, parental mental health, family trauma, and stressful life events), and individual factors. This chapter includes a discussion of the risk and protective factors accounting for AI/AN youth mental health disparities, implications for correcting disparities and the importance of incorporating familial and community level interventions for AI/AN youth.