Heterozygous loss-of-function mutation of the calcium sensing-receptor (CaSR), causes familial hypocalciuric hypercalcemia (FHH), a typically benign condition characterized by mild hypercalcemia. In contrast, homozygous mutation of this dimer-forming G-protein coupled receptor manifests as the lethal neonatal severe hyperparathyroidism (NSHPT). To investigate the mechanisms by which CaSR mutations lead to these distinct disease states, we engineered wild-type (WT) and disease-causing CaSR mutations into the cDNA, and transfected expression constructs into human embryonic kidney (HEK) cells. WT protein was primarily membrane-expressed whereas the mutant CaSR protein was distributed throughout the cytoplasm. Co-expression of WT CaSR directed mutant CaSR to the cell membrane. In assays of CaSR function at physiological extracellular [Ca²⁺] ([Ca²⁺]_o), increases in [Ca²⁺]_o increased intracellular [Ca²⁺] ([Ca²⁺]_i) in cells expressing wild-type CaSR while the response was moderately reduced in cells transfected with mutant and WT receptor. Untransfected cells and those expressing mutant receptor alone, both showed minimal but equivalent responses when stimulated with increased [Ca²⁺]_o. Both the [Ca²⁺]_i response and the CaSR membrane density were linearly related to the plasmid DNA concentration used for transfection. Equimolar transfection of WT and mutant CaSR resulted in protein membrane levels that were predicted by random association. Immunoprecipitation experiments confirmed that these mutant and wild-type CaSR associate in a complex. Taken together these data indicate CaSR self-associates to form a dimer, and that mutant receptor heterodimerization with WT receptor completely rescues the trafficking defect by directing it to the cell surface. Function of the WT and mutant homodimeric receptors and the heterodimeric receptors were then explored under conditions designed to minimize desensitization. To determine the function of the heterodimeric receptor, and affinity for [Ca²⁺]_o, we subtracted the WT homodimer response (25%) expected for the random assortment of hetero- and homodimers following equal co-expression. The maximal response to [Ca²⁺]_o was dependent on CaSR membrane level and not whether the receptors were homo- or heterodimers. The affinity of the WT CaSR was three times greater than that of the heterodimer (EC₅₀ of 2.5 ± 0.1 mM versus 7.2 ± 0.7 mM). In summary, these results suggest that heterodimerization of WT and mutant CaSR receptors, rescues the trafficking defect of half the mutant receptors and also results in a lower affinity for Ca²⁺ by the WT-mutant heterodimer. In contrast the homozygous mutant does not produce functional receptors on cell membrane. These data indicate major differences in the mechanisms producing FHH and NSHPT.