Environmental heat stress undermines efficient animal production resulting in a significant financial burden to agricultural producers. The reduction in performance during heat stress is traditionally thought to result from reduced nutrient intake. Recently, this notion has been challenged with observations indicating that heat-stressed animals may exploit novel homeorhetic strategies to direct metabolic and fuel selection priorities independent of nutrient intake or energy balance. Alterations in systemic physiology support a shift in metabolism, stemming from coordinated interactions at whole-body and tissue-specific levels. Such changes are characterized by increased basal and stimulated circulating insulin concentration in addition to the ostensible lack of basal adipose tissue lipid mobilization coupled with reduced adipocyte responsiveness to lipolytic stimuli. Hepatic and skeletal muscle cellular bioenergetics also exhibit clear differences in carbohydrate production and use, respectively, due to heat stress. The apparent dichotomy in intermediary metabolism between the 2 tissue types may stem from factors such as tricarboxylic acid cycle substrate flux and mitochondrial respiration. Thus, the heat stress response markedly alters postabsorptive carbohydrate, lipid, and protein metabolism through coordinated changes in fuel supply and use across tissues in a manner that is distinct from commonly recognizable changes that occur in animals on a reduced plane of nutrition. Perhaps most intriguing is that the coordinated systemic, cellular, and molecular changes appear conserved across physiological states and among different ruminant and monogastric species. Ultimately, these changes result in the reprioritization of skeletal muscle fuel selection during heat stress, which may be important for whole-body metabolism and overall physiological adaptation to hyperthermia.