High-altitude environments provide natural experimental settings to investigate adaptation to environmental stress. An important evolutionary and functional question is whether sea-level human biology constrains the adaptive response. This paper presents evidence that indigenous populations of the Tibetan and Andean plateaus exhibit quantitatively different responses to hypobaric hypoxic stress. At the same altitude, Tibetan mean resting ventilation and hypoxic ventilatory response were more than one-half standard deviation higher than Andean Aymara means while Tibetan mean oxygen saturation and hemoglobin concentration were more than one standard deviation below the Andean means. Quantitative genetic analyses of the familial patterning of these traits provided indirect evidence of population differences in genes influencing them. The Tibetan and Andean patterns of oxygen transport appear equally effective functionally as evaluated by birthweight and maximal aerobic capacity across a range of altitudes.