This article reports findings from three qualitative studies exploring supports for positive transitions of American Indian/Alaska Native (AI/AN) youth to adulthood. Community-based participatory methods were employed through a research partnership involving a culturally based community agency, the Native American Youth and Family Center (NAYA), the National Indian Child Welfare Association, and Portland State University. Studies utilized a Relational Worldview (RWV) framework, where well-being is understood as a balance among the domains of mind, body, spirit, and context. Collectively, findings demonstrate that NAYA employs culturally grounded interventions to overcome the traumatic histories and current oppressive conditions affecting low-income urban AI/AN youth with mental health challenges and to support their well-being and transition to adulthood. In addition, addressing the mental health and well-being of AI/AN youth in culturally appropriate ways involves consideration of all RWV domains. Recommendations for behavioral health practice are to connect AI/AN youth to culturally specific services whenever possible, utilize cultural consultants, and implement holistic and positive approaches to mental health.