Due to the importance of Ca2+ in the regulation of vital cellular and tissue functions, the concentration of Ca2+ in body fluids is closely guarded by an efficient feedback control system. This system includes Ca2+-transporting subsystems (bone, intestine, and kidney), Ca2+ sensing, possibly by a calcium-sensing receptor, and calcium-regulating hormones (parathyroid hormone [PTH], calcitonin [CT], and 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3]). In humans and birds, acute Ca2+ perturbations are handled mainly by modulation of kidney Ca2+ reabsorption and by bone Ca2+ flow under PTH and possibly CT regulation, respectively. Chronic perturbations are also handled by the more sluggish but economic regulatory action of 1,25(OH)(2)D-3 on intestinal calcium absorption. Peptide hormone secretion is modulated by Ca2+ and several secretagogue:;. The hormones' signal is produced by interaction with their respective receptors, which evokes the cAMP and phospholipase C-IP3-Ca2+ signal transduction pathways. 1,25(OH)(2)D-3 operates through a cytoplasmic receptor in controlling transcription and through a membrane receptor that activates the Ca2+ and phospholipase C messenger system. The calciotropic hormones also influence processes not directly associated with Ca2+ regulation, such as cell differentiation, and may thus affect the calcium-regulating subsystems also indirectly.