Maximal VO2 (VO2max) has mostly been the province of exercise physiologists wishing to provide a measure of athletic potential or to characterize subjects in exercise-related research. It is also used clinically to determine a patient's exercise capacity. More recently, it has been recognized that the study of VO2max can provide fundamental insight into O2 transport at all points between inspired air and muscle mitochondria. This review focuses on understanding how VO2max is set and concludes that the more athletic one is, the more VO2max is sensitive to O2 transport conductances in the lungs, circulation, and skeletal muscle. These transport conductances form an integrated system, all components interacting to define VO2max. A particularly important component is diffusive conductance in muscle. This appears to be abnormal in chronic conditions such as obstructive pulmonary disease and heart and renal failure and may well explain why correction of central cardiovascular defects in O2 transport in such patients fails to restore exercise capacity.