All stages of the O2 transport pathway are affected in some way by both acute and chronic altitude exposure. At any one stage, the effects are multiple, sometimes subtle, and frequently opposing. Clear-cut differences in responses to acute and to chronic altitude exposure are detectable but not in every case explainable, leaving important and perplexing problems still to be solved. Perhaps the most interesting of these relate to control of cardiac output and to determinants of O2 diffusion from muscle capillary red cells to the muscle mitochondria.