This paper proceeds as follows: the first section describes the scope of the fentanyl crisis among AI/AN communities and the critical inadequacy of existing data. The second section highlights regional variations in fentanyl/drug poisonings in AI/AN populations and explores a set of possible explanatory drivers, including the adoption of Public Law 83-280, conferring general criminal jurisdiction over the lands of Native nations to state-level authorities, rates of incarceration, and access to medication for treating opioid use disorder. Next, the paper discusses AI/AN innovative responses to the fentanyl crisis, including cultural connectedness and new ways to expand access to medications for opioid use disorder. The paper also explores the existing state and federal obstacles to the design and implementation of these AI/AN factors, thereby explaining the disproportionately high rates of suicide among AI/AN youth, including contemporary socio-economic factors and long-term marginalization and exploitation, and ways to reduce those risks, such as through greater exercise of tribal self-government. The paper concludes with policy recommendations.