Specialized cells (i.e., parathyroid chief cells) that sense changes in the extracellular calcium concentration are a key element in mineral ion homeostasis. The Ca2+o-sensing receptor (CaR) originally cloned from bovine parathyroid is also present in multiple nephron segments involved in Ca2+o homeostasis as well as in other sites that are not, such as brain, lung, large and small intestine. The physiological relevance of the CaR has been established by identifying hyper- and hypocalcemic disorders resulting from CaR mutations: familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism result from inactivating CaR mutations, while an autosomal dominant form ofhypocalcemia is caused by activating mutations. In addition to sensing Ca2+o and Mg2+o abnormally (the latter suggesting the CaR acts as an Mg2+o-sensing receptor), persons with FHH have alterations in their handling of water, supporting a role for the CaR in integrating mineral ion and water metabolism. Drugs that activate the CaR ('calcimimetics') are currently undergoing clinical trials and will permit pharmacological manipulation of the receptor when it functions abnormally (e.g., in primary hyperparathyroidism).