The indigenous populations of high altitude, physiologically with lower concentration of hemoglobin and higher level of nitric oxide, can be well-adapted to hypoxia and cold environment. Recent studies have revealed that these adaptive highland population possessed genetic bases, which involved a number of genes, such as EPAS1, EGLN1, CBARA1, VAV3, PPARA, and eNOS, associating with hypoxia-inducible pathway, production of red blood cells and vasodilator substances, etc. These findings provided new insights and strategies from genetics to uncover the unique natural environment selection, to understand the mechanisms of plateau diseases, finally to better prevent and treat them.