The extracellular calcium-sensing receptor (CaSR) is the first identified G protein-coupled receptor to be activated by an ion, extracellular calcium (Ca(2+)). Since the identification of the CaSR in 1993, genetic mutations in the CaSR gene, and murine models in which CaSR expression has been manipulated, have clearly demonstrated the importance of this receptor in the maintenance of stable, free, ionized Ca(2+) concentration in the extracellular fluids. These functions have been extensively reviewed elsewhere. However, the distribution pattern and expression of the CaSR in lower vertebrates strongly suggest that the CaSR must play a role that is independent of mineral cation metabolism. This review addresses the involvement of the CaSR in nutrient sensing; its putative and demonstrated functions during conception, embryonic development, and birth; and its contributions to adult physiology and disease, with reference to CaSR-based therapeutics. Recent ongoing developments concerning the role of the CaSR in stem cell differentiation are also reviewed.