Just what determines maximum O2 uptake (VO2max) has been the subject of much study and discussion over the years, with agreement among investigators still beyond reach. However, the evidence that in normal man VO2max is limited generally by the supply of O2 is substantial. Turning to the well-known steps of the pathway for O2 from atmosphere to mitochondria, the question then becomes how these steps in fact set the limit to VO2max. This presentation will stress two related hypotheses on how VO2max is set: 1) all steps in the O2 pathway interact in a manner that determines VO2max, such that an increase (decrease) in the transport capacity for any one step predictably increases (decreases) VO2max, and 2) a major component of this process is the rate at which O2 can move by diffusion from Hb in the red cell to the muscle mitochondria. A graphical analysis of this integrative hypothesis is presented with supporting data to show how all transport steps contribute to VO2max. This analysis ties together the ideas and data presented by the other speakers in this symposium, and also leads to predictions that are testable by feasible experiments.