Rapid ascent to high altitude may cause serious problems for climbers, skiers, and aviators. In contrast, gradual ascent enables humans to function where the unacclimatized cannot. To examine changes in the O2 transport system that produce acclimatization, eight men were taken in a decompression chamber (without other stresses experienced on high mountains) to a simulated altitude of 8,840 m (29,028 ft, ambient PO2 = 43 Torr) in 40 days. Maximal O2 uptake fell to 1.2 l/min, and arterial PO2 and PCO2 were 30 and 11 Torr, respectively, with arterial pH of 7.56. Many sophisticated studies were done: Swan-Ganz catheterization and inert gas diffusion studies at three altitudes showed that normal cardiac function persisted, pulmonary vascular resistance increased and at extreme altitude was not lowered by O2, and pulmonary ventilation-perfusion mismatch increased, though variably. This appears to be an important factor limiting performance at extreme altitude. This paper presents the background, general approach, and a summary of major observations reported in detail in other papers.