Resistance to O2 diffusion is reflected in the difference in pO2 between O2 reservoirs of hemoglobin (Hb) and myoglobin. The very low normal myocyte pO2 (less than one torr but adequate for optimal oxidative ATP synthesis) compared to venous pO2 indicates that blood does not achieve equilibrium with tissue during its passage through capillaries. In the lung, diffusion rate of O2 from alveolus to capillary is normally sufficient to achieve essential equilibrium. However, system-wide capillary pathology and reduced Hb saturation has been observed with distal local ischemia. In peripheral vascular disease (PVD) patients, we found a mean arterial pO2 of 77 torr (normal over 90 torr). Classical concepts based on "tissue pO2" values derived from venous blood or oxygen electrodes inserted into tissue need re-evaluation. Readings of O2 electrodes moved through tissue range widely from intracapillary levels down toward intracellular levels and do not reflect the pO2 of any particular site. Intravenous pO2 is the result of residual O2 after incomplete diffusion out of capillaries during transit through a tissue, and is not an equilibrium value with some tissue pool. The effect of HbO2 p50 on oxygen release during the passage of blood through a capillary bed, generally judged on the basis of percentage percent saturation at "tissue pO2", should be judged on the basis of the change in pO2 (the diffusion driving force) associated with a particular degree of HbO2 saturation at a particular p50. The thesis that O2 diffusion rate is a major determinant of oxygen delivery is supported by pO2 responses to treatment of PVD that does not alter blood flow or p50.