Medical problems occur at high altitude because of the low inspired Po(2), which is caused by the reduced barometric pressure. The classical physiological responses to high altitude include hyperventilation, polycythemia, hypoxic pulmonary vasoconstriction-increased intracellular oxidative enzymes, and increased capillary density in muscle. However, with the discovery of hypoxia-inducible factors (HIFs), it is apparent that there is a multitude of responses to cellular hypoxia. HIFs constitute a master switch determining the general response of the body to oxygen deprivation. The recent discovery of genetic changes in Tibetans has opened up an exciting area of research. The two major human populations that have adapted well to high altitude, the Tibetans and Andeans, have strikingly different phenotypes. Diseases of lowlanders going to high altitude include acute mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. Diseases affecting permanent residents or highlanders include chronic mountain sickness and high-altitude pulmonary hypertension. Important recent advances have been made on mitigation of the effects of the hypoxic environment. Oxygen enrichment of room air is very powerful. Every 1% increase in oxygen concentration reduces the equivalent altitude by about 300 m. This procedure is used in numerous facilities at high altitude and in a Chinese train to Lhasa. An alternative strategy is to increase the barometric pressure as in aircraft cabins. A hybrid approach combining both strategies shows promise but has never been used. Mines that are being developed at increasingly high altitudes pose great medical problems.