The parathyroid glands play a key role in maintaining near constancy of the extracellular calcium concentration ( Ca(o)2+) through their capacity to sense even minute changes in the level of blood calcium from its normal level. The G protein-coupled, Ca(o)(2+)-sensing receptor (CaSR) is the mechanism through which the parathyroid chief cells senses changes in Ca(o)2+. In primary hyperparathyroidism (PHPT), Ca(o)2+ is reset upward from its normal level. This defect likely arises from increases in both the mass of pathological parathyroid tissue as well as the set point for Ca(o)(2+)-regulated parathyroid hormone (PTH) release. The former likely arises from somatic mutations that enhance parathyroid cellular proliferation, although our understanding of the mechanism(s) underlying the latter is incomplete. However, substantial insights have been achieved through the study of inherited disorders caused by mutations in CaSR gene. In familial hypocalciuric hypercalcemia (FHH), heterozygous inactivating mutations in the CaSR gene produce mild, generally asymptomatic hypercalcemia, whereas in neonatal severe hyperparathyroidism (NSHPT), homozygous inactivating mutations cause severe hypercalcemia and hyperparathyroidism. Thus, the body's "calciostat" is reset upward in FHH and NSHPT because of resistance of CaSR-expressing cells, including the parathyroid cells, to Ca(o)2+. In FHH, there is a reduced complement of normal CaSRs (e.g., haploinsufficiency) that likely provides an explanation for the Ca(o)(2+)-resistance in this condition, whereas in NSHPT, there are no normally functioning CaSRs, thereby engendering more severe Ca(o)2+ resistance. Although somatic mutations in the CaSR gene could provide an explanation for the Ca(o)(2+)-resistance in PHPT, no such mutations have been found. Instead, in PHPT, the resistance of pathological parathyroid glands to Ca(o)2+ results, at least in part, from a reduced expression of otherwise apparently structurally normal CaSRs. Thus, PTH-dependent hypercalcemia can occur in the setting of either inherited, generalized resistance to Ca(o)2+ (i.e., FHH and NSHPT) or acquired tissue selective resistance of pathological parathyroid glands to Ca(o)2+ (e.g., PHPT).