The calcium-sensing receptor (CaSR) is a nutrient-sensing receptor that mediates feedback regulation of systemic calcium homeostasis in fetal and postnatal life, and also plays key roles in cell fate determination (survival, proliferation and differentiation) acting to support complex development programs for diverse organs including the CNS and lung (1). In this respect the receptor provides a ‘switch’ function that arises firstly from its expression in the presence of activating concentrations of Ca2+ and other nutrients, and secondly from local or systemic modulation of nutrient levels. The CaSR’s more general role in nutrient sensing arises from its membership of the taste receptor sub-group of GPCR class C. This it senses not only Ca2+ and Mg2+ ions but also L-amino acids (review: (2)) by which it plays roles in coordinating gastrointestinal responses to ingested dietary protein e.g., via stimulating the release of enteric hormones including gastrin, cholecystokinin, GLP, GIP and PYY. To achieve these diverse roles the CaSR exhibits ligand-directed (biased) signaling by which certain but not all ligands are restricted in their access to specific signaling pathways. The most striking comparison is between Ca2+ and L-Phe. Ca2+ activates all known pathways downstream of the receptor and its interactions with Gq/11, Gi/o and G12/13. L-Phe, on the other hand, activates a restricted set of signaling pathways downstream of Gq/11 and Gi/o that appear to limit its actions primarily to the acute control of peptide hormone secretion. The mechanisms that underlie these physiologically important restrictions on L-amino acid-dependent signaling are starting emerge and appear to include not only the adoption of ligand-specific receptor conformations but also posttranslational modifications such as PKC-dependent phosphorylation of CaSR residue T888. The physiological significance of amino acid dependent signaling is being revealed in transgenic mice in which the CaSR’s sensing functions for L-amino acids and Ca2+o have been dissociated.