The system governing extracellular calcium (Ca²⁺_o) homeostasis maintains near constancy of Ca²⁺_o so as to ensure continual availability of calcium ions for their numerous intracellular and extracellular roles. In contrast to the intracellular ionized calcium concentration (Ca²⁺_i), which varies substantially during intracellular signaling via this key second messenger, Ca²⁺_o remains nearly invariant. Yet there must be a mechanism that senses small changes in Ca²⁺_o so as to set into motion the homeostatic responses that return Ca²⁺_o to its normal level. The recent identification and molecular cloning of the mechanism through which parathyroid cells and a number of other cell types sense Ca²⁺_o, a G protein-coupled Ca²⁺_o-sensing receptor (CaR), has proven unequivocally that extracellular calcium ions serve in an informational capacity. The CaR permits Ca²⁺_o to function in a hormone-like role as an extracellular first messen-ger through which parathyroid, kidney, and other cells communicate with one another via the CaR. The identification of inherited human hypercalcemic and hypocalcemic disorders arising from inactivating and activating mutations of the CaR, respectively, has provided additional proof of the essential, nonredundant role of the CaR in mineral ion homeostasis. Moreover, CaR-active drugs are currently in clinical trials for the treatment of primary and uremic hyperparathyroidism, disorders in which there are acquired, tissue-specific reductions in CaR expression and, in turn, defective Ca²⁺_o-sensing by pathological parathyroid cells. No doubt further studies of Ca²⁺_o-sensing by the CaR will reveal additional functions of Ca²⁺_o, not only as a systemic “hormone” but also in local, paracrine, and autocrine signaling through this novel Ca²⁺_o-sensing receptor.