Among ethnic groups in the United States, American Indian and Alaska Native (AI/AN) children experience the highest rates of injury mortality and morbidity. Injury mortality rates for AI/AN children have decreased during the past quarter century, but remain almost double the rate for all children in the United States. The Indian Health Service (IHS), the federal agency with the primary responsibility for the health care of AI/AN people, has sponsored an internationally recognized injury prevention program designed to reduce the risk of injury death by addressing community-specific risk factors. Model programs developed by the IHS and tribal governments have led to successful outcomes in motor vehicle occupant safety, drowning prevention, and fire safety. Injury prevention programs in tribal communities require special attention to the sovereignty of tribal governments and the unique cultural aspects of health care and communication. Pediatricians working with AI/AN children on reservations or in urban environments are strongly urged to collaborate with tribes and the IHS to create community-based coalitions and develop programs to address highly preventable injury-related mortality and morbidity. Strong advocacy also is needed to promote childhood injury prevention as an important priority for federal agencies and tribes.