Although it has been generally well-accepted since the work of August Krogh at the start of the 20th century that O2 travels between muscle microvascular red cells and muscle mitochondria by diffusion, the importance of this process to maximal O2 flux remains in question. This review presents data that suggest maximal rates of diffusion of O2 in muscle are limited by both the amount of capillary structure and the haemoglobin concentration in the blood. On the other hand, diffusional conductance appears unrelated to muscle fibre size and thus to distance. Functional data further suggest that the limited rate of diffusion acts to constrain O2 unloading from muscle capillaries and thus also maximal Vo2, at least in the trained state. In fact, the calculated sensitivity of VO2max to muscle diffusional conductance is about as great as that for muscle blood flow. While additional impairment of O2 unloading from perfusion/metabolism heterogeneity cannot yet be excluded (for lack of methodology), it seems evident that the process of O2 transport between the muscle microvasculature and the mitochondria is subject to significant limits, even in health, that have substantial effects on maximal Vo2.