Thermoregulatory mechanisms are remarkably efficient, ensuring minimal temperature variation within the core of the human body under physiological conditions. Diverse afferent and efferent neural pathways contribute to the monitoring of core and skin temperature, generation of heat, and control of thermal exchange with the external environment. We have investigated the cortical, thalamic, and hypothalamic responses to cooling and warming by using positron-emission tomography activation imaging of subjects clad in a water-perfused suit, which enabled rapid change of their skin-surface temperature. Human brain regions that respond to changes in skin temperature have been identified in the somatosensory cortex, insula, anterior cingulate, thalamus, and hypothalamus, with evidence that the hypothalamic response codes for the direction of temperature change. We conclude that signals from thermosensors in the skin providing crucial afferent information to the brain are integrated with signals from central thermosensors, resulting in thermoregulatory responses that maintain core temperature within a remarkably narrow range.