The human extracellular Ca2+-sensing receptor (CaR) plays a key role in the regulation of serum calcium and parathyroid hormone. This large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites. Positive allosteric modulators of the CaR, which increase CaR activation and thereby decrease secretion of parathyroid hormone, are potential for the treatment of primary and secondary hyperparathyroidism. Conversely, negative allosteric modulators of the CaR, which decrease the receptor activation and thereby stimulate endogenous parathyroid hormone secretion, are potential for the treatment of osteoporosis and autosomal dominant hypocalcemia. Significant progress has been made in recent years in screening for allosteric modulators selectively targeting the CaR and identification of receptor residues important for allosteric modulation.