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The desert frog Neobatrachus pelobatoides reduced its resting metabolism in vivo by 60-70% during 5-7 weeks of aestivation (summer dormancy). The rate of oxygen consumption (V(O2)) of isolated and intact skeletal muscle, measured in vitro, was 70% lower for aestivating frogs compared with non-aestivating frogs. The cause of the reduced V(O2) of aestivating frog muscle must lie in the tissue itself rather than being induced by external factors such as oxygen supply or blood-borne metabolites (because these were identical in the in vitro assay conditions), by any short-term effects produced by hormones (as these would have been washed out of the tissues during incubation) or by tissue dehydration (as the tissues from aestivating frogs had rehydrated to non-aestivating levels). The reduced in vitro muscle VO2 accounted for 60-77% of the frogs in vivo metabolic depression that accompanied aestivation. Other tissues of the aestivating frog, namely intestine, liver, skin and fat, did not have a reduced in vitro VO2. We suggest that metabolic depression is initiated by reduced energy demand in cells and this consequently leads to reduced energy production.