Free fatty acids (FFAs) are essential nutrients. An ever-increasing number of studies have demonstrated that FFAs are important signaling molecules as well, contributing to many cellular functions. FFAs have been found to activate several G protein–coupled receptors (GPCRs), which are named free fatty acid receptors (FFARs), including G protein–coupled receptor 40 (GPR40 aka FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), GPR84, GPR119, and GPR120 (FFAR4). The FFAR’s are a critical component of the body’s nutrient sensing apparatus, and small molecule agonists and antagonists of these receptors show considerable promise in the management of obesity, dyslipidemia, and diabetes. Unlike the classic ‘lock and key’ relationship between receptors and their ligands, nutrient receptors are considered to be promiscuous in that they can be activated by a range of ligands.