Free fatty acids (FFAs) are not only essential nutritional components, but they also act as signaling molecules in various physiological processes. Recently, a G-protein-coupled receptor deorphanizing strategy has successfully identified a family of receptors that are activated by FFAs. FFA receptors (FFARs) are proposed to play critical roles in a variety of physiological and pathophysiological processes, especially in metabolic disorders. Among the FFARs, FFAR1 (GPR40) and GPR120 are activated by medium- and long-chain FFAs. FFAR1 facilitates glucose-stimulated insulin secretion from pancreatic β-cells, whereas GPR120 regulates the secretion of glucagon-like peptide-1 in the intestine, as well as insulin sensitivity in macrophages. Because these receptors are potential therapeutic targets for metabolic disorders such as type 2 diabetes, selective ligands have been developed. In this review, we discuss recent advances in the identification of ligands, structure activity relationships, and pharmacological characterization of FFAR1 and GPR120, and we present a summary of recent progress in understanding their physiological roles and their potential as drug targets. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3594–3601, 2011