High-altitude natives have distinctive biological characteristics that appear to offset the stress of hypoxia. Evolutionary theory reasons that they reflect genetic adaptations resulting from natural selection on traits with heritable variation. Furthermore, high-altitude natives of the Andean and Tibetan Plateaus differ from one another, perhaps resulting from different evolutionary histories. Three approaches have developed a case for the possibility of population genetic differences: comparing means of classical physiological traits measured in samples of natives and migrants between altitudes, estimating genetic variance using statistical genetics techniques, and comparing features of species with different evolutionary histories. Tibetans have an inferred autosomal dominant major gene for high oxygen saturation that is associated with higher offspring survival, a strong indicator of ongoing natural selection. New approaches use candidate gene and genomic analyses. Conclusive evidence about population genetic differences and associations with phenotypes remains to be discovered.