Low ambient partial pressures of oxygen at high altitudes result in low alveolar and arterial partial pressures that stress physiological oxygen delivery systems. People moved onto high-altitude plateaus in three areas of the world in the past 10,000 or more years, resulting in independent natural experiments in adaptation and evolution. Unexpectedly, the high-altitude native populations of the Andean, Tibetan and East African plateaus have different suites of adaptive traits and their genomes show different signatures of natural selection despite the common stress. This talk presents aspects of the three patterns of adaptation, their relative costs and benefits, and evidence that they result from evolutionary processes. The variety of responses to the same stress expands our understanding of oxygen homeostasis.