Fatty acids are produced through various biological processes. Free fatty acids (FFAs) are mainly provided from long- and medium-chain fatty acids derived from dietary triglycerides, and short-chain fatty acids (SCFAs) produced by microbial fermentation of the otherwise indigestible dietary fiber. A strategy to deorphanize G-protein-coupled receptors (GPCRs) previously identified a series of receptors, which are activated by FFAs. Hence, FFAs are now recognized as not only essential nutritional components but also signaling molecules in various physiological processes. A number of recent studies showed that a group of GPCRs sensing FFAs, which are termed free fatty acid receptors (FFARs), play significant roles in nutritional and immune regulation. In these FFARs, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain FFAs, whereas FFAR3 (GPR41) and FFAR2 (GPR43) are activated by SCFAs. In this symposium, I will introduce recent advances on the key physiological functions of the FFARs-mediated signaling transduction pathways in the regulation of metabolism and immune responses. I will further present a summary of current understandings of their pharmacological characterization and their potential as drug targets.