The calcium-sensing receptor (CaSR) belongs to the evolutionarily conserved family of plasma membrane G protein-coupled receptors (GPCRs). Early studies identified an essential role for the CaSR in systemic calcium homeostasis through its ability to sense small changes in circulating calcium concentration and to couple this information to intracellular signaling pathways that influence parathyroid hormone secretion. However, the presence of CaSR protein in tissues is not directly involved in regulating mineral ion homeostasis points to a role for the CaSR in other cellular functions including the control of cellular proliferation, differentiation and apoptosis. This position at the crossroads of cellular fate designates the CaSR as an interesting study subject is likely to be involved in a variety of previously unconsidered human pathologies, including cancer, atherosclerosis and Alzheimer's disease. Here, we will review the recent discoveries regarding the relevance of CaSR signaling in development and disease. Furthermore, we will discuss the rational for developing and using CaSR-based therapeutics.