The calcium-sensing receptor (CaSR) controls parathyroid hormone (PTH) secretion, which, in turn, via direct and indirect actions on kidney, bone, and intestine, maintains a normal extracellular ionized calcium concentration (Ca²⁺_o). There is less understanding of the CaSR's homeostatic importance outside of the parathyroid gland. We have employed single and double knockout mouse models, namely mice lacking PTH alone (CaSR^+/+ PTH^−/−, referred to as C⁺P⁻), lacking both CaSR and PTH (CaSR^−/− PTH^−/−, C⁻P⁻) or wild-type (CaSR^+/+ PTH^+/+, C⁺P⁺) mice to study CaSR-specific functions without confounding CaSR-mediated changes in PTH. The mice received three hypercalcemic challenges: an oral Ca²⁺ load, injection or constant infusion of PTH via osmotic pump, or a phosphate-deficient diet. C⁻P⁻ mice show increased susceptibility to developing hypercalcemia with all three challenges compared with the other two genotypes, whereas C⁺P⁻ mice defend against hypercalcemia similarly to C⁺P⁺ mice. Reduced renal Ca²⁺ clearance contributes to the intolerance of the C⁻P⁻ mice to Ca²⁺ loads, as they excrete less Ca²⁺ at any given Ca²⁺_o than the other two genotypes, confirming the CaSR's direct role in regulating renal Ca²⁺ handling. In addition, C⁺P⁺ and C⁺P⁻, but not C⁻P⁻, mice showed increases in serum calcitonin (CT) levels during hypercalcemia. The level of 1,25(OH)₂D₃ in C⁻P⁻ mice, in contrast, was similar to those in C⁺P⁻ and C⁺P⁺ mice during an oral Ca²⁺ load, indicating that increased 1,25(OH)₂D₃ production cannot account for the oral Ca²⁺-induced hypercalcemia in the C⁻P⁻ mice. Thus, CaSR-stimulated PTH release serves as a “floor” to defend against hypocalcemia. In contrast, high-Ca²⁺_o-induced inhibition of PTH is not required for a robust defense against hypercalcemia, at least in mice, whereas high-Ca²⁺_o-stimulated, CaSR-mediated CT secretion and renal Ca²⁺ excretion, and perhaps other factors, serve as a “ceiling” to limit hypercalcemia resulting from various types of hypercalcemic challenges.