The series of drops in PO2which comprise the oxygen cascade from the air to mammalian tissue can provide useful information about O2transport during exercise in both health and disease, but the complete cascade has been challenging to studyin vivo. This paper reviews a series ofin vivohuman knee-extensor studies which focus on the determinants of maximal O2consumption (˙VO2max) in exercising muscle and concludes with a characterization of the complete O2cascade in maximally exercising human muscle. Specifically, three issues have been addressed: 1) determinants of O2extraction under conditions of very high muscle blood flow; 2) the role of O2diffusivity in determining the maximum O2flux rate(˙VO2max); and 3) myoglobin associated PO2as a indicator of O2transport and cellular respiration rate. In summary, these investigations demonstrate that in humans O2extraction can be uncompromised despite high mass specific blood flows, perhaps in part because of an increased capillary density in exercise trained subjects. Exercise in hypoxia reduces ˙VO2max, but as calculated diffusability of O2from blood to muscle is constant this suggests that a fixed O2diffusivity plays a key role in limiting maximal O2uptake. Supporting evidence of a substantial PO2gradient from blood to myoglobin also suggests a resistance to the diffusion of O2between red cell and sarcolemma, which may be present even at submaximal exercise. Finally, the proportionate relationship between myoglobin associated PO2and ˙VO2maxin conditions of normoxia and hypoxia additionally supports the hypothesis that maximal respiratory rate of muscle cells is limited by O2supply.