The extracellular Ca2+-sensing receptor is a member of the G-protein-coupled receptor family 3 in which agonists bind to a dimeric Venus-flytrap domain in the extracellular portion of the receptor. How agonist binding to this domain leads to activation of the seven-transmembrane domain is a major unresolved question. Information derived from the three-dimensional structure of the Venus-flytrap domain of the related metabotropic glutamate type 1 receptor, and from naturally occurring mutations of the Ca2+-sensing receptor identified in subjects with familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia offers new insights into the mechanism of receptor activation, and into the mechanism of action of allosteric modulators of the receptor.