The extracellular calcium-sensing receptor (CaR) plays key roles in maintaining extracellular calcium homeostasis by enabling several of the cells and tissues involved in this process to sense small changes in Ca(2+)(o) and to respond with changes in cellular function that will restore Ca(2+)(o) to its normal level. The chief cells of the parathyroid gland and the thyroidal C-cells, for example, respond to decreases in Ca(2+)(o) with increased secretion of the Ca(2+)(o)-elevating hormone, parathyroid hormone (PTH), and decreased secretion of the Ca(2+)(o)-lowering hormone, calcitonin, respectively. The cells of the renal distal tubule are likewise capable of sensing Ca(2+)(o) and respond to decreases in Ca(2+)(o) with increased tubular reabsorption of Ca(2+) and vice versa, alterations in tubular function that will contribute to normalization of Ca(2+)(o). The skeleton also plays key roles in maintaining Ca(2+)(o) homeostasis and both osteoblasts and osteoclasts can sense Ca(2+)(o), with elevations in Ca(2+)(o) promoting bone formation and inhibiting bone resorption. It has been suggested that Sr(2+) could act on bone via the CaR; however, the molecular mechanisms through which Ca(2+)(o) and Sr(2+)(o) exert these actions on bone cells remain controversial. Therefore, identifying their molecular target(s) would have significant implications for the treatment of bone loss. Ideally, therapies should simultaneously inhibit bone resorption while stimulating bone formation. Administration of strontium produces exactly those effects. Previous studies with dispersed bovine parathyroid cells as well as a preliminary study using CaR-transfected Chinese hamster ovary (CHO) cells indicate that Sr(2+)(o) is an agonist of the CaR, albeit with slightly lower efficacies and potencies than Ca(2+)(o). Given that Sr(2+)(o) is distributed preferentially in bone, therefore, an action of this divalent cation on the CaR in bone cells represents one possible mechanism by which strontium ranelate, a new antiosteoporotic drug, exerts it skeletal actions in vivo.