In their journey into the Americas, the ancestors of present-day Indigenous peoples overcame extraordinary challenges. Genomes from some contemporary Indigenous peoples reveal genetic variation attributable to contact with Europeans following their arrival in the Americas in 1492. These developments have greatly increased the number of genomes from ancient peoples, and new methods for analyzing ancient genomes have helped us better understand the stories they tell. At the time of this writing, there are perhaps several dozen publicly available complete genomes from contemporary and ancient Indigenous peoples. There are few complete genomes from the present-day U.S., the result of Indigenous peoples’ justified distrust in researchers.