In 2004 we reported the cloning of a novel mammalian family C G-protein coupled receptor, termed GPRC6A. The subsequent objective was to identify the endogenous ligands for the receptor, develop the first selective antagonist and unravel its physiological function. The molecular pharmacology of the receptor was determined by expression in Xenopus oocytes and HEK293 cells. Pharmacological responses were measured by electrophysiology and inositol phosphate generation, respectively. The first selective antagonists were discovered using a chemogenomic approach which identified 2-phenyl-indoles as potential antagonists, which were subsequently purchased/synthesized and tested pharmacologically. The physiological function of the receptor was determined by generation and analyses of a GPRC6 receptor knockout mouse. Measurement of calcium-dependent chloride currents in Xenopus laevis oocytes and inositol phosphate generation in HEK293 cells facilitated the deorphanization of GPRC6A and identification of L-alpha-amino acids as agonists. The most active agonists were basic L-alpha-amino acids, L-arginine, L-lysine and L-ornithine. The receptor is widely expressed in human and mouse tissue, including a range of tissues relevant to metabolism regulation. Based on chemogenomic predictions, 25 2-phenyl-indole analogs were purchased/synthesized and tested pharmacologically. 3 compounds were found to be selective GPRC6A receptor antagonists. The GPRC6A mouse was generated by ablation of exon 6 coding the 7-transmembrane domain and was backcrossed to C57BL/6. The mice show no obvious phenotype on regular chow, but do show a phenotype related to exercise/metabolism in more complex scenarios. We have identified a novel receptor promiscuously activate by L-amino acids. We have developed the first selective antagonists, and shown that the receptor is potentially involved in regulating functions related to exercise/metabolism.