It is commonly observed that during acclimatization to altitude oxidative enzyme activities increase per g wet weight of tissue. To examine this problem in long-term adapted animals we measured citrate synthase (CS), hydroxyacylCoA dehydrogenase (HOAD), pyruvate kinase (PK), and lactate dehydrogenase (LDH) activities/g of myocardium in two domestic species (llama and alpaca) and a high altitude deer, the taruca. In all these species, we found an upward scaling of oxidative capacity (indicated by absolute activities of CS and HOAD) but a downward scaling of anaerobic/aerobic metabolic potentials of the heart (indicated by low ratios of LDH/CS, and LDH/HOAD, but high ratios of PK/LDH). As the direction and magnitude of these long-term adaptations are the same as in shorter-term acclimatizations, we wondered why a similar pattern at the enzyme level correlates with the right shift of the O2 dissociation curve (ODC) in the latter case, but with a left shifted ODC in the former. We hypothesize that in the long term, increased oxidative enzyme activities allow increased maximum flux capacity of aerobic metabolism. This in turn calls for physiological adjustments in O2 transfer systems; flux limits of the former must be matched by flux limits of the latter. Only then can an acceptably high scope for aerobic activity be achieved despite reduced O2 availability in inspired air. Such long-term match-up invariably calls for a left-shifted ODC plus other well known adjustments in O2 transport. In the short term, right shifting the ODC may increase the total amount of aerobic work possible (by favoring O2 unloading and thus raising tissue O2 concentration), yet maximum flux capacity cannot be changed much because mitochondrial metabolism is designed for maintaining stable rates of ATP synthesis even at widely varying O2 tensions. That is why even in short-term acclimatization, in order to increase flux capacity, the activities of oxidative enzymes also must be increased.