Calcium ions serve multiple biological roles; therefore, maintaining a nearly constant extracellular ionized calcium concentration (Ca2,) is a critical function of free-living terrestrial organisms. Tetrapods have evolved a homeostatic system for accomplishing this goal that has two key elements [1] (Fig. 1): The first are cells that sense (that is, recognize and respond to) small physiologically-relevant changes in Ca2, including parathyroid cells and thyroidal C-cells, which secrete, respectively, less parathyroid hormone (PTH) and more calcitonin (CT) in the presence of elevated levels of Ca20 [1, 21. The second element are the effector tissues that translocate Ca20 ions in response to calciotropic hormones (that is, kidney, bone and intestine) [1, 2]. The receptor-mediated mechanisms through which classical calciotropie hormones, such as PTH, calcitonin and 1,25-dihydroxyvitamin D regulate their target tissues has been the focus of intense studies. In contrast, much less has been known until recently about the mechanisms underlying Ca20-sensing by parathyroid and C-cells. Recent application of molecular techniques, however, has shown that Ca2)-sensing, like the sensing of many other extracellular first messengers, involves a cell surface, Ca20sensing receptor (CaR) that is a member of the superfanuly of G-protein-coupled receptors (GPCR) [3]. Moreover, the receptor is present not only in classic Ca20-sensing cells, like parathyroid cells, but also in effector elements of the mineral ion homeostatic system, such as the kidney [3, 4]. Finally, studies on the role of the CaR in inherited diseases of Ca20-sensing have yielded novel insights into the basis for previously poorly understood direct actions of Ca20 on renal function.