Germline knockout of the extracellular Ca²⁺-sensing receptor (CaR) leads to a phenotype that includes severe hypercalcemia, hyperparathyroidism, relative hypocalciuria, skeletal abnormalities, retarded growth, and early postnatal death. To investigate the role of heterotrimeric G proteins in CaR signaling, we used cre/lox technology to delete the respective α-subunits of G_q and G₁₁ selectively in parathyroid cells. Mice that were PTH-Cre^+/−; Gnaq^flox/flox; Gna11^−/− (PTH-Gα_q/Gα₁₁-double knockouts) were viable, but showed all the features of germline knockout of the CaR except hypocalcuria. Our results demonstrate the critical role of both G_q and G₁₁ in mediating inhibition of PTH secretion by extracellular Ca²⁺.