The systematic increase in O2 uptake and O2 extraction with increasing work rates conceals a substantial heterogeneity of O2 delivery (Q˙O2)-to-V˙O2 matching across and within muscles and other organs. We hypothesize that whether increased/decreased Q˙O2/V˙O2 heterogeneity can be judged as "good" or "bad", for example after exercise training or in aged individuals or with disease (heart failure, diabetes), depends on the resultant effects on O2 transport and contractile performance.Summary statementMuscle Q˙O2/V˙O2 heterogeneity may be key to subserving different regional exercise O2 demands in health but derangements in disease may be detrimental to blood-myocyte O2 flux and contractile performance in disease states.