In the beginning there was no oxygen (O2) on planet Earth, today the atmosphere hosts 21%, after considerable oscillations of it through millions of years. Over time, living organisms evolved by mounting mechanisms to detect and respond to fluctuations in O2 concentration in their internal environment. Oxygen sensors in the carotid body, and the HIF system in all cells, play a crucial role in maintaining O2 homeostasis at the organism and cellular level. Therefore, in normoxia, HIFs are rapidly synthesized and destroyed, but in hypoxia, their degradation is inhibited. HIFs, regulate protein expression to compensate for hypoxia, increasing O2 delivery to tissues, and reducing O2 consumption. Millions of people live at high altitudes, such as in the Andean and Tibetan plateaus. Newborns in these regions weigh less than those in the lowlands, but this difference in Tibetans is smaller than in the Andeans. There is a greater increase in utero­placental blood flow in Andean and Tibetan women compared to pregnancies in Europeans, at the same altitude. These increases are due to synthesis in NO and PGI2, generated by HIFs. The Andean populations display Chronic Mountain Sickness (CMS), characterized by increase in hemoglobin concentration, diminution of PO2 and pulmonary hypertension. In contrast, the Tibetans do not have these conditions due to polymorphisms of two genes, the EPAS-1 that encodes for HIF-2a, expressing polymorphisms with loss-of-function and the EGLN-1 gene that encodes for prolyl hydroxylase-2, with gain-of-function polymorphisms, thus reducing HIFs tasks, decreasing hemoglobin concentration and pulmonary arterial hypertension.