This brief review examines the athletic potential of mammals in general and the horse in particular as it relates to oxygen (O2) transport and utilization. The horse has been bred selectively for over six millennia based upon its ability to run fast. Whereas this has optimized cardiovascular and muscle function and the capacity to deliver and utilize O2, it has resulted in lung failure during intense exercise. Horses in their athletic prime are considered and attention is focused on their maximal capacities as related to O2 transport, irrespective of age per se. Following a few comments on the history of O2, this review moves from established principles of O2 transport at the integrative organ level to the microcirculation and the processes and principles that govern O2 offloading, where much remains to be discovered. Four principal questions are addressed: (1) as an athlete, what are the most outstanding physiological characteristics of the horse? (2) what anatomical and physiological capacities facilitate this superlative performance and such prodigious O2 fluxes (i.e. maximal VO2)? (3) do cardiovascular dynamics or intramuscular energetic processes limit VO2 kinetics (i.e. the speed at which VO2 increases at the onset of exercise)? VO2 kinetics determine the size of the O2 deficit and as such represent an important determinant of muscle metabolism and fatigue; and (4) what determines the efficacy of muscle microcirculatory O2 exchange?