Heat exchange processes between the body and the environment are introduced. The definition of the thermoneutral zone as the ambient temperature range within which body temperature (Tb) regulation is achieved only by nonevaporative processes is explained. Thermoreceptors, thermoregulatory effectors (both physiologic and behavioral), and neural pathways and Tb signals that connect receptors and effectors into a thermoregulation system are reviewed. A classification of thermoeffectors is proposed. A consensus concept is presented, according to which the thermoregulation system is organized as a dynamic federation of independent thermoeffector loops. While the activity of each effector is driven by a unique combination of deep (core) and superficial (shell) Tbs, the regulated variable of the system can be viewed as a spatially distributed Tb with a heavily represented core and a lightly represented shell. Core Tb is the main feedback; it is always negative. Shell Tbs (mostly of the hairy skin) represent the auxiliary feedback, which can be negative or positive, and which decreases the system's response time and load error. Signals from the glabrous (nonhairy) skin about the temperature of objects in the environment serve as feedforward signals for various behaviors. Physiologic effectors do not use feedforward signals. The system interacts with other homeostatic systems by "meshing" with their loops. Coordination between different thermoeffectors is achieved through the common controlled variable, Tb. The term balance point (not set point) is used for a regulated level of Tb. The term interthreshold zone is used for a Tb range in which no effectors are activated. Thermoregulatory states are classified, based on whether: Tb is increased (hyperthermia) or decreased (hypothermia); the interthreshold zone is narrow (homeothermic type of regulation) or wide (poikilothermic type); and the balance point is increased (fever) or decreased (anapyrexia). During fever, thermoregulation can be either homeothermic or poikilothermic; anapyrexia is always a poikilothermic state. The biologic significance of poikilothermic states is discussed. As an example of practical applications of the concept presented, thermopharmacology is reviewed. Thermopharmacology uses drugs to modulate specific temperature signals at the level of a thermoreceptor (transient receptor potential channel).