Calcium homeostasis in vertebrates is regulated by hormonal communication between the parathyroid and thyroid glands, kidney, bone, and intestine. A central mediator of this regulatory system is the calcium sensor CaS (also known as CaR), a class III GPCR that is activated by high concentrations of extracellular calcium and other divalent cations. The cell types that are responsive to variations in blood calcium concentration express CaS and respond to changes in extracellular calcium in a CaS-dependent fashion. Activation of CaS in parathyroid chief cells inhibits PTH release, which results in decreased calcium mobilization from bone. In contrast, stimulation of CaS activity in the C cells of the thyroid increases secretion of calcitonin, which causes decreased bone resorption and increased urinary excretion of calcium. Allosteric "calcimimetic" potentiators are being evaluated for treatment of primary hyperparathyroidism.