American Indian and Alaska Native (AI/AN) populations have substantial health inequities, and most of their disease entities begin in childhood. In addition, AI/AN children and adolescents have excessive disease rates compared with the general pediatric population. Because of this, providers of pediatric care are in a unique position not only to attenuate disease incidence during childhood but also to improve the health status of this special population as a whole. This policy statement examines the inequitable disease burden observed in AI/AN youth, with a focus on toxic stress, mental health, and issues related to suicide and substance use disorder, risk of and exposure to injury and violence in childhood, obesity and obesity-related cardiovascular risk factors and disease, foster care, and the intersection of lesbian, gay, bisexual, transgender, queer, and Two-Spirit and AI/AN youth. Opportunities for advocacy in policy making also are presented.* Contributed equally as co-first authors Drs Bell, Deen, Fuentes, and Moore were equally responsible for conceptualizing, writing, and revising the manuscript, while also considering input from all reviewers; and all authors approved the final manuscript as submitted.Policy statements from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However, policy statements from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent. The guidance in this statement does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.