The extracellular calcium-sensing receptor (CaR) is a seven transmembrane–spanning G-protein–coupled receptor. It contains a large extracellular domain (ECD), the signature seven transmembrane domains (TMDs), three intracellular loops, and a large carboxy terminal tail. The CaR is expressed in the parathyroid, thyroid C-cells, kidney, brain, pituitary, intestine, bone marrow, skin, and other tissues. CaRs regulate serum calcium homeostasis through changes in parathyroid hormone (PTH) levels and renal calcium excretion. CaRs may also participate in controlling cell growth and differentiation, and in augmenting the actions of other hormones. Autosomal dominant hypocalcemia is caused by gain-of-function mutations that increase the sensitivity of the CaR to Ca2+.Familial benign hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism result from inactivating mutations of the CaR. The locations of the point mutations that are responsible for both increased and decreased sensitivity to extracellular Ca2+are typically in the ECD of the CaR, supporting the idea that the ECD is responsible for both Ca2+binding and sensing changes in Ca2+. Binding of Ca2+to the ECD may cause a conformational change in the ECD that promotes an interaction with critical TMD residues, thus enhancing G-protein–dependent signal transduction. A class of compounds called calcimimetics potentiates the effects of extracellular Ca2+on the CaR.Calcimimetics have been shown to reduce PTH and serum Ca2+in patients with primary (1°) and secondary (2°) hyperparathyroidism (HPT). Studies with rats suggest that calcimimetics may be useful in treating renal osteodystrophy and may also suppress parathyroid growth. Further long-term studies will be needed to address the possible benefit of calcimimetics to patients with 1° and 2° HPT.