Throughout the body, amino acid sensing mechanisms couple protein ingestion to physiological responses including the control of growth, tissue maintenance, and digestion and absorption. The molecular identities of the amino acid sensors in endocrine glands, the gut, kidney and other tissues, however, have been unclear. Recent work demonstrates that several class 3 G-protein coupled receptors (GPCRs) are broad-spectrum amino acid sensors that couple increases in amino acid levels to the activation of phospholipase C and intracellular Ca2+ mobilization. The calcium-sensing receptor (CaR) is one broad-spectrum amino acid sensor of the class 3 sub-group with apparent selectivity for aromatic, aliphatic and polar amino acids. Its most potent amino acid activators include L-Phe and L-Trp, which are recognized activators of gastrin and gastric acid secretion as well as cholecystokinin and attendant pancreatic enzyme secretion. Based on considerations of fasting and fed amino acid concentrations, however, it is apparent that the CaR exhibits equivalent responses to as many as 6-8 amino acids and is highly sensitive to changes in the integrated plasma amino acid concentration. With respect to intracellular Ca2+ mobilization, the CaR responds to both extracellular Ca2+ (Ca2+o) and amino acids and exhibits strong positive interactions between the two classes of activators. In the human parathyroid, which expresses the CaR at high levels endogenously, CaR-active amino acids markedly promote intracellular Ca2+ mobilization and reversibly suppress the secretion of the key calcium-regulating peptide hormone, PTH. Human adenomatous parathyroid cells, which exhibit markedly reduced CaR expression when compared to normal cells, however, are much less sensitive to amino acids. Recent work suggests that thyroid parafollicular C-cells, which secrete another calcium-regulating peptide hormone calcitonin under CaR control, are also sensitive to acute changes in amino acid concentrations. In the gut, CaR expression is widespread, potentially explaining diverse effects of calcium ions and aromatic amino acids on digestion and epithelial transport. For example, gastric parietal cells exhibit marked positive interactions between Ca2+ and the aromatic amino acid L-Phe with respect to gastric acid secretion. The CaR is also widely expressed in the kidney, and recent work demonstrates that L-Phe stimulates renal calcium excretion, consistent with CaR-dependent inhibitory regulation of calcium reabsorption in the cortical thick ascending limb. Taken together, the results indicate that the CaR, as well as several other closely related class 3 GPCRs, represent physiologically and, potentially medically, significant targets for L-amino acids.