At high-altitude, hypobaric hypoxia is a significant stress for humans and other animals, challenging oxygen homeostasis and therefore tissue metabolism. Genetic signals of physiological adaptation have been identified in human populations and non-human species with long-term residence at high-altitude. In Tibetans, some genetic signals are linked to altered metabolic function, e.g. variants in EPAS1 are associated with increased glycolysis, whilst variants in PPARA are associated with a decreased capacity for fatty acid oxidation. A number of other genetic signals that may impact on metabolism have been identified in Tibetans and other populations, although the downstream consequences are not well-defined. Use of high-throughput technologies to comprehensively profile metabolic phenotype could advance understanding of the evolutionary processes conferring hypoxia tolerance at high-altitude.