The mechanisms underlying sweet taste in mammals have been elusive. Although numerous studies have implicated G proteins in sweet taste detection, the expected G protein-coupled receptors have not been found. Here we describe a candidate taste receptor gene, T1r3, that is located at or near the mouse Sac locus, a genetic locus that controls the detection of certain sweet tastants. T1R3 differs in amino acid sequence in mouse strains with different Sac phenotypes ('tasters' versus 'nontasters'). In addition, a perfect correlation exists between two different T1r3 alleles and Sac phenotypes in recombinant inbred mouse strains. The T1r3 gene is expressed in a subset of taste cells in circumvallate, foliate and fungiform taste papillae. In circumvallate and foliate papillae, most T1r3-expressing cells also express a gene encoding a related receptor, T1R2, raising the possibility that these cells recognize more than one ligand, or that the two receptors function as heterodimers.