Biologists usually refer to mammals and birds as homeotherms, but these animals universally experience regional and temporal variations in body temperature. These variations could represent adaptive strategies of heterothermy, which in turn would favor genotypes that function over a wide range of temperatures. This coadaptation of thermoregulation and thermosensitivity has been studied extensively among ectotherms, but remains unexplored among endotherms. In this review, we apply classical models of thermal adaptation to predict variation in body temperature within and among populations of mammals and birds. We then relate these predictions to observations generated by comparative and experimental studies. In general, optimality models can explain the qualitative effects of abiotic and biotic factors on thermoregulation. Similar insights should emerge when using models to predict variation in the thermosensitivity of endotherms, but the dearth of empirical data on this subject precludes a rigorous analysis at this time. Future research should focus on the selective pressures imposed by regional and temporal heterothermy in endotherms.