Parathyroid cells, C-cells, and certain cells in the kidney express a cell surface calcium (Ca2+) receptor which enables these cells to detect and respond to changes in the concentration of extracellular Ca2+. This receptor protein is a member of the G protein-coupled receptor superfamily and shares limited sequence homology only with metabotropic glutamate receptors. The Ca2+ receptor is the primary physiological mechanism regulating the secretion of parathyroid hormone (PTH) and plays a pivotal role in maintaining systemic Ca2+ homeostasis. Compounds that act as Ca2+ receptor agonists are called calcimimetics because they mimic or potentiate the effects of extracellular Ca2+ on parathyroid cell function. NPS R-568 is a small organic calcimimetic compound that acts as a positive allosteric modulator to increase the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. In normal rats, orally administered NPS R-568 decreases plasma levels of PTH and Ca2+ and, at higher doses, increases plasma levels of calcitonin. The changes in the circulating levels of these two hormones explain the hypocalcemia caused by this compound. NPS R-568 also effectively lowers plasma PTH levels in normal humans and in rat models of secondary hyperparathyroidism. Calcimimetic compounds that target the Ca2+ receptor provide a novel therapeutic approach for treating primary and secondary hyperparathyroidism.