The importance of intracellular calcium in regulating cell function is well recognized. No less important, but less well understood (and probably appreciated), is the fundamental role played by extracellular calcium, Ca2+o, in the modulation of cell function. The recent cloning of Ca2+o-sensing, G-protein-coupled receptors from bovine (and human) parathyroid and rat kidney (and brain) has clearly demonstrated that Ca2+o can function as a traditional 'first messenger'. The identification of 'inactivating' and 'activating' mutations in this Ca2+o-sensing receptor in two hypercalcemic disorders and in an autosomal dominant form of hypocalcemia, respectively, has underscored the physiological relevance of this receptor in Ca2+ homeostasis in man. These advances have significantly enhanced our understanding of the molecular mechanisms involved in extracellular calcium sensing in parathyroid and kidney. Moreover, the localization of the Ca2+o-sensing receptor in tissues previously not known to have Ca2+o-sensing capability has suggested novel and potentially quite important roles for Ca2+o in regulating the function of cells not apparently directly involved in Ca2+ homeostasis.