Certain environmental stressors can impair cellular ATP production to the point of harming or even killing an animal. Some exceptional animals employ strategies that maintain the balance between ATP production and consumption, allowing them to tolerate prolonged exposure to stressors such as hypoxia and anoxia. Anoxia- and hypoxia-tolerant animals reduce ATP consumption by ion-motive ATPases while concomitant reductions in passive ion flux reduce the demand for ion pumping and maintain transmembrane ion gradients. Reductions in gene transcription and protein turnover decrease ATP demand in hibernating and hypoxia-tolerant animals. Proton leak uncouples mitochondrial substrate oxidation from ATP synthesis and accounts for a considerable proportion of cellular energy demand, but there is little evidence that the proton permeability of inner mitochondrial membranes decreases in animals that tolerate energy stress. Indeed in some cases proton leak increases, possibly reducing reactive oxygen species production. Because substrate oxidation is important to the control of cellular metabolism, the downregulation of ATP supply pathways contributes significantly to metabolic suppression under energy stress. Mechanisms that coordinate the downregulation of both ATP supply and demand pathways include AMP kinase and ATP-sensitive ion channels. Strategies employed by animals tolerant to one energy stress often convey "cross-tolerance" to completely different stresses.