CaSR, the extracellular Calcium-Sensing Receptor, is a widely expressed G-protein coupled receptor (GPCR) involved in calcium homeostasis. CaSR operates as a sensor in parathyroid and kidney, and alterations in its activity have been shown to cause thyroid disease in humans. Activation of the receptor in response to extracellular calcium or other ligands causes activation of phospholipase C (PLC), release of IP3 and release of calcium from intracellular stores. Proinflammatory cytokines IL-1β and TNF-α increase CaSR gene expression in human thyroid and kidney cells through activation of the NF-κB pathway, and this pathway may be involved in hypocalcemia often seen in critically ill patients. Elevated calcium concentration and CaSR expression have been linked to proliferation and metastasis of skeletal metastatic prostate cancer cell lines. In intestinal epithelial cells, CaSR is involved in regulation of cyclic nucleotide metabolism and the fluid secretion that results in life-threatening fluid loss in response to intestinal pathogens. The interaction of CaSR with the actin-binding protein filamin may provide scaffolding for the organization of signaling pathways converging on the cytoskeleton, including CaSR-mediated MAPK pathway activation.