High-altitude headache is one of many neurological symptoms associated with the ascent to high altitudes. Cellular hypoxia due to decreased barometric pressure seems to be the common final pathway for headache as altitude increases. Susceptibility to high-altitude headache depends on genetic factors, history of migraine, and acclimatization, but symptoms of acute mountain sickness are universal at very high altitudes. This review summarizes the pathophysiology of acute mountain sickness and high-altitude headache as well as the evidence for treatment and prevention with different drugs and devices which may be useful for regular and novice mountaineers. This includes an examination of other headache disorders which may mimic high-altitude headache.