The Ca(2+)-sensing receptor (the CaSR), a G-protein-coupled receptor, regulates Ca(2+) homeostasis in the body by monitoring extracellular levels of Ca(2+) ([Ca(2+)]o) and responding to a diverse array of stimuli. Mutations in the Ca(2+)-sensing receptor result in hypercalcemic or hypocalcemic disorders, such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and autosomal dominant hypocalcemic hypercalciuria. Compelling evidence suggests that the CaSR plays multiple roles extending well beyond not only regulating the level of extracellular Ca(2+) in the human body, but also controlling a diverse range of biological processes. In this review, we focus on the structural biology of the CaSR, the ligand interaction sites as well as their relevance to the disease associated mutations. This systematic summary will provide a comprehensive exploration of how the CaSR integrates extracellular Ca(2+) into intracellular Ca(2+) signaling.