The role of the calcium-sensing receptor (CaR), a G-protein-coupled receptor, is that of a calcium thermostat. The receptor regulates the synthesis and the secretion of the parathyroid hormone. The CaR is expressed not only in the parathyroid glands but also in the gut, the kidneys, and the bone cells. These three organs are the major components in the calcium homeostasis. The CaR regulates cell differentiation, proliferation, and membrane potentials in many other tissues both normal and malignant. Functionally important mutations in the CaR lead to changes in the calcium homeostasis and diseases. Mutations which improve the sensitivity lead to a familial form of hypocalcemia, while mutations which decrease the sensitivity cause hypercalcemia. Interestingly, reports on autoimmune antibodies causing a state of hypercalcemia have just been published. In secondary hyperparathyroidism the CaR has now become a target for treatment.