Extracellular Ca(2+) concentration [Ca(2+)](o) is vital for a number of processes varying from blood clotting to regulation membrane permeability and excitability. For this reason [Ca(2+)](o) is under strict control of a complex homeostatic system that includes parathyroid glands, kidneys, bones and intestine. The extracellular Ca(2+)-sensing receptor is an essential component of this system, regulating parathyroid hormone secretion, Ca(2+) (and Mg(2+)) excretion by the kidney, bone remodeling and Ca(2+) reabsorption by the gastrointestinal tract. The Ca(2+)-sensing receptor is also present in organs without an obvious link with mineral ion metabolism. This review will describe the discovery of a novel class of ion-sensing receptor(s), receptor-effector coupling and the roles of the Ca(2+)-sensing receptor inside and outside the Ca(2+)(o) homeostatic system.