The G protein-coupled receptors FFA1 (previously designated GPR40) and FFA4 (previously GPR120) are both activated by saturated and unsaturated longer-chain free fatty acids. With expression patterns and functions anticipated to directly or indirectly promote insulin secretion, provide homeostatic control of blood glucose and improve tissue insulin sensitivity, both receptors are being studied as potential therapeutic targets for the control of type II diabetes. Furthermore, genetic and systems biology studies in both humans and mouse models link FFA4 to diabetes and obesity. Although activated by the same group of free fatty acids, FFA1 and FFA4 are not closely related and whilst the basis of recognition of fatty acids by FFA1 is similar to that of the short-chain fatty acid receptors FFA2 and FFA3, amino acid residues involved in endogenous ligand recognition by FFA4 are more akin to those of the sphingosine 1 phosphate receptor S1P1 . Screening and subsequent medicinal chemistry programmes have developed a number of FFA1 selective agonists that are effective in promoting insulin secretion in a glucose concentration-dependent manner, and in lowering blood glucose levels. However, the recent termination of phase III clinical trials employing TAK-875/Fasiglifam has caused a setback and raises important questions over the exact nature and mechanistic causes of the problems. Progress in the identification and development of highly FFA4-selective pharmacological tools has been less rapid and several issues remain to be clarified to fully validate this receptor as a therapeutic target. Despite this the ongoing development of a range of novel ligands offers great opportunities to further unravel the contributions of these receptors.