This review attempts to provide insights into factors associated with fatigue in human and nonhuman animals by using the two fundamental approaches of comparative physiology: determining common principles that govern structure and function in animals that are relatively invariant between animals and evaluating animals that have been highly adapted by natural selection to demonstrate extreme performance. In this review, I approach the topic of fatigue by considering factors that are associated with its reciprocal or inverse or duration of sustained performance before fatigue sets in to end the performance. The two general factors that I consider that affect endurance time more than any other are body temperature and body mass. The former affects endurance time because of thermodynamic effects on chemical reaction rates and metabolism; the latter acts through the mechanism of allometry or scaling. The examples of extreme animal performance that I discuss are two examples of bird migration, the diving performance of marine mammals, and the unique relationship that governs energy cost of locomotion in hopping kangaroos.