Publisher Summary This chapter examines the importance of G-protein-coupled, extracellular Ca 2+ -sensing receptor as a versatile regulator of diverse cellular functions. In the extracellular space, calcium is a cofactor for clotting factors, adhesion molecules, and other proteins. It also regulates neuronal excitability and is an essential component of the mineral phase of the skeleton. Bone provides both a structural framework protecting crucial bodily structures and enabling locomotion and a large reservoir of mineral ions that can be mobilized in times of need. The maintenance of near constancy of Ca 2+ in tetrapods necessitates that specific cells of the mineral ion homeostatic system detect and respond in a homeostatically appropriate manner to the changes in plasma calcium concentration of the same order as its normal variability. Elevated levels of Ca 2+ also stimulate several aspects of osteoblast function in vitro that could promote increased bone formation in vivo and, therefore, reductions in Ca 2+ . The evidence for the presence of a G-protein-coupled CaR came from studies in bovine parathyroid cells examining the actions of Ca 2+ , the physiological agonist for the putative CaR, on intracellular second messengers. A variety of polyvalent cations mimic the actions of Ca 2+ on the osteoclast, but their pharmacological profile in this cell type differs distinctly from that in parathyroid and other CaR-expressing cells.