We discuss the relevance of comparative physiology to aspects of temperature regulation, and the problems of extrapolating from animal models to humans. Students of comparative physiology learn detail of size scaling laws in animal energetics, including laws that describe the effect of body size on heat exchange and on the thermoneutral zone. Much of the research on animal models of human disease, including genetic risk models, is done on rodents maintained at 22-23°C, a temperature well below a rodent’s thermoneutral zone. In some disease domains this experimental anomaly may not matter, but the increase in metabolism and decrease in RQ (indicative of increased fat oxidation) that occurs below the thermoneutral zone may confound extrapolations to humans in any disease with a metabolic component. Another medical issue topical currently is whether isolated cooling of the traumatized human brain is feasible, the study of which is confounded by the difficulty of measuring deep brain temperature in healthy humans. Based on studies of many other species, we show that capacity for selective brain cooling depends on the carotid rete, a structure that humans and other primates do not possess, rendering it improbable that humans can implement selective brain cooling. The primary determinant of brain temperature is the temperature of the blood reaching it. If the temperature of blood destined for the brain is manipulated, isolated cooling of the brain is possible. Cooling the head without cooling the blood destined for the brain does not result in isolated brain cooling. e-mail: shane.maloney@uwa.edu.au