Studies of native high-altitude residents, who have been challenged by hypoxia for hundreds of generations, provide the unique opportunity to identify and link genetic adaptations to physiological changes in an extreme environment. Previous research has shown that highland populations from different continents and non-native highlanders respond to altitude in different ways, yet a great deal remains to be learned about the mechanisms underlying this variation. Most humans living at altitudes above 4000 meters develop polycythemia, classically considered an adaptive response to enhance oxygen transport at altitude. It is therefore surprising to find that many healthy Tibetan highland natives are not polycythemic. Recent genomic analyses show that Tibetans have several genetic adaptations to high altitude and haplotypes harboring a few of these genes, including those involved in the hypoxia inducible factor pathway (EPAS1, EGLN1, and PPARA), are further associated with loss of polycythemia (Simonson et al. 2010; Beall et al. 2010; Yi et al. 2010). Several genes reported in more than one genomic analysis of Tibetan adaptation (e.g. HMOX2, CYP17A1, PKLR, HFE, and HBB/HBG2 gene regions [Wuren et al. 2014]) have not as of yet been associated with traits exhibited by this population but warrant further analysis in a physiological genomics context. In order to determine the physiological relevance, genetic underpinnings, and sequence of adaptive events in Tibetans, we are examining exercise capacity and oxygen transport, the precise genetic targets that afford evolutionary advantages, and the relationships among these factors and relatively lower hemoglobin levels (loss of polycythemia) in adapted Tibetans. This natural experiment in human adaptation has broad implications for understanding evolutionary processes and provides important insight into hypoxia sensing and response in humans at altitude and in oxygen-limited disease states.