The extracellular calcium ion (Ca²⁺_e)-sensing receptor (CaR) enables key tissues that maintain Ca²⁺_e homeostasis to sense changes in the Ca²⁺_e concentration. These tissues respond to changes in Ca²⁺_e with functional alterations that will help restore Ca²⁺_e to normal. For instance, decreases in Ca²⁺_e act via the CaR to stimulate secretion of parathyroid hormone—a Ca²⁺_e-elevating hormone—and to increase renal tubular calcium reabsorption; each response helps promote normalization of Ca²⁺_e levels. Further work is needed to determine whether the CaR regulates other parameters of renal function (e.g. 1,25-dihydroxyvitamin D₃ synthesis, intestinal absorption of mineral ions, and/or bone turnover). Identification of the CaR has also elucidated the pathogenesis and pathophysiology of inherited disorders of mineral and electrolyte metabolism; moreover, acquired abnormalities of Ca²⁺_e-sensing can result from autoimmunity to the CaR, and reduced CaR expression in the parathyroid may contribute to the abnormal parathyroid secretory control that is observed in primary and secondary hyperparathyroidism. Finally, calcimimetics—allosteric activators of the CaR—treat secondary hyperparathyroidism effectively in end-stage renal failure.