In mammals Ca2+ concentration in the extracellular fluids ([Ca2+]o) is essential for a number of vital processes varying from bone mineralization to blood coagulation, regulation of enzymatic processes, modulation of permeability and excitability of plasma membranes. For this reason [Ca2+]o is under strict control of a complex homeostatic system that includes parathyroid glands, kidneys, bones and intestine. The extracellular Ca(2+)-sensing receptor (CaR) is an essential component of this system, regulating parathyroid hormone secretion, calcium (and magnesium) excretion by the kidney, bone remodeling and Ca2+ reabsorption by the gastrointestinal tract. Structurally, the CaR is a novel member of a growing G protein-coupled receptor superfamily, which includes metabotropic glutamate receptors (mGluRs) [1], [gamma]-aminoisobutyric acid (GABA-B) receptors [2] and vomeronasal organ receptors [3]. Initially identified from bovine parathyroid glands [4], within the 5 years following its identification CaR presence has rapidly been identified as extending to organs where the link with mineral ion metabolism has not been elucidated (i.e. brain, stomach, eye, skin and many other epithelial cells) (see [5] for review). The role of the receptor in these regions is largely unknown, but it appears to be somewhat related to phenomena such as chemotaxis, cell proliferation and programmed cell death. This review will describe the discovery of a novel class of ion-sensing receptor(s), receptor-effector coupling and the roles of the CaR inside and outside the Ca2+o homeostatic system.