The regulation of body temperature is one of the most critical functions of the nervous system. Here we review our current understanding of thermoregulation in mammals. We outline the molecules and cells that measure body temperature in the periphery, the neural pathways that communicate this information to the brain, and the central circuits that coordinate the homeostatic response. We also discuss some of the key unresolved issues in this field, including the following: the role of temperature sensing in the brain, the molecular identity of the warm sensor, the central representation of the labeled line for cold, and the neural substrates of thermoregulatory behavior. We suggest that approaches for molecularly defined circuit analysis will provide new insight into these topics in the near future. Tan and Knight review the neural mechanisms that regulate body temperature in mammals. They describe the molecules and cells that sense temperature, the afferent pathways that transmit this information to the brain, and efferent pathways that coordinate the homeostatic response.