Indigenous youth in many countries face high levels of mental health problems, including suicide. While many of the relevant strategies for the promotion of mental health and well-being and the prevention of mental disorders are similar to those for youth in other contexts, there are some unique challenges and opportunities for Indigenous populations and communities. These include the histories of colonization, cultural suppression, and marginalization that have profoundly affected many communities across multiple generations as well as the distinctive ways of life and current social and geographic contexts that shape the values and aspirations of youth and their families. These historical and social structural issues contribute to specific social determinants of health and illness, influence well-being and resilience, and have important implications for mental health promotion. In this chapter, we review some of the salient features of Indigenous contexts and characteristics that affect the well-being of Indigenous youth. We outline an approach to mental health promotion that takes into account historical, transgenerational, and contemporary contexts and seeks to build on the strength and resilience of Indigenous communities and youth. Our examples come from Canada but have broader application for Indigenous peoples in many countries as well as for youth from other marginalized communities that have faced historical loss and devaluation and must meet the challenges of globalization and ongoing culture change.