Important conceptual changes concerning human thermoregulation have occurred in the last decade. While the hypothalamus maintains its central role in sensing core temperature and providing connectivity to orchestrate heat loss and cold defense autonomic neuronal mechanisms, it is now regarded as one of multiple, independent thermoeffector pathways that control core body temperature. Recent research in primate central and peripheral thermosensitivity has emphasized the importance of temperature-activated transient receptor potential (TRP) channels and afferent neuronal pathways from peripheral thermosensors that are activated by unique combinations of core and shell temperature. The interoceptive aspects of behavioral thermoregulation have been emphasized including the primary importance of shell (skin) temperature, the concept of thermal discomfort and the important contribution of orbitofrontal, insular, somatosensory, and amygdala cortical regions deployed to anticipate and avoid thermal stress. Clinical testing of human thermoregulation requires afferent stimuli to activate the independent thermoeffector loops while monitoring an efferent response. Patterns of sweat gland activation, amount of sweat produced, and areas of anhidrosis demonstrated by the thermoregulatory and axon reflex sweat testing provide diagnostic information about neurological and medical disorders of the autonomic nervous system.