The taste system is made of taste cells clustered in taste buds which are embedded in taste papillae at the surface of the tongue. Taste sensations are elicited when sweeteners, salts, acids, bitter or umami molecules activate specific receptors expressed in taste cells and initiate a signal transduction cascade. The perception of dietary fat is based mainly on texture, viscosity and olfaction, but there is increasing evidence that the taste system also plays a role. Triglycerides, the main components of oils and other dietary fats are hydrolyzed by the lingual lipase into free fatty acids, which are detected by the gustatory system. GPR40 and GPR120 are G-protein coupled receptors (GPCRs) that respond in vitro to medium and long chain fatty acids. We showed by immunohistochemistry and PCR that both GPCRs are expressed in mouse taste cells. GPR120 is expressed in circumvallate, foliate and fungiform papillae, mainly in type II cells. GPR40 is expressed in circumvallate and foliate but very rarely in fungiform papillae, mainly in type I cells. To determine if those GPCRs play a role in fat taste signal transduction, we carried out behavioral and nerve recording studies on GPR40 and GPR120 knockout mice. Compared with control mice, single knockout mice have diminished preference and intake for intralipid, oleic acid and linoleic acid (n=10-15 per group). Whole taste nerve recordings showed a diminished response to lingual application of several fatty acids in the glossopharyngeal and chorda tympani nerves for GPR120 KO mice and only in the glossopharyngeal nerve for GPR40 KO mice compared to wild type mice (n=6-9 per group). Preference tests comparing wild type, single and double KO mice showed that GPR40 is the main GPCR mediating fat preference in mice (n=10 per group).