Whether maximal oxygen uptake (&OV0312;O2max) during exercise in healthy subjects reflects limitation of the supply of oxygen to muscle mitochondria or an inability to use oxygen beyond some biochemical limit remains debated. This paper summarizes evidence for the hypothesis that &OV0312;O2maxis limited by O2supply. How the many steps in the pathway for oxygen interact to determine maximum oxygen supply is analyzed, resulting in a mathematical model of predictive value. A major component of this model is the diffusional transport of oxygen out of the muscle microcirculation. The proportionality between &OV0312;O2maxand the capillary to mitochondrion partial pressure gradient (as FIO2is altered) supports this hypothesis, but does not exclude the existence of convective heterogeneity of blood flow as a factor contributing to the limitation of &OV0312;O2max. Although there is no direct method for measuring convective heterogeneity, altering hemoglobin P50permits distinguishing diffusive from convective elements in limiting &OV0312;O2max, and both the underlying theory and the results are summarized herein. Our conclusion is that &OV0312;O2maxin health appears limited by the supply of oxygen to the mitochondria, which in turn, depends upon the integrated interaction among all of the diffusive and convective steps in the oxygen pathway between the environment and the mitochondria.