Indigenous peoples in the United States are diverse and distinct political and cultural groups and populations. Though they may be affected by climate change in ways that are similar to others in the United States, Indigenous peoples can also be affected uniquely and disproportionately. Many Indigenous peoples have lived in particular areas for hundreds if not thousands of years. Indigenous peoples’ histories and shared experience engender distinct knowledge about climate change impacts and strategies for adaptation. Indigenous peoples’ traditional knowledge systems can play a role in advancing understanding of climate change and in developing more comprehensive climate adaptation strategies. Observed and projected changes of increased wildfire, diminished snowpack, pervasive drought, flooding, ocean acidification, and sea level rise threaten the viability of Indigenous peoples’ traditional subsistence and commercial activities that include agriculture, hunting and gathering, fisheries, forestry, energy, recreation, and tourism enterprises. Despite institutional barriers to tribal self-determination stemming from federal trust authority over tribal trust lands, a number of tribes have adaptation plans that include a focus on subsistence and commercial economic activities. Some tribes are also pursuing climate mitigation actions through the development of renewable energy on tribal lands. Climate impacts to lands, waters, foods, and other plant and animal species threaten cultural heritage sites and practices that sustain intra- and intergenerational relationships built on sharing traditional knowledges, food, and ceremonial or cultural objects. This weakens place-based cultural identities, may worsen historical trauma still experienced by many Indigenous peoples in the United States, and adversely affects mental health and Indigenous values-based understandings of health. Throughout the United States, climate-related disasters are causing Indigenous communities to consider or actively pursue relocation as an adaptation strategy. Challenges to Indigenous actions to address disaster management and recovery, displacement, and relocation in the face of climate change include economic, social, political, and legal considerations that severely constrain their abilities to respond to rapid ecological shifts and complicate action toward safe and self-determined futures for these communities.