Three closely related, FFA1-3, and two further, GPR84 and GPR120, G protein-coupled receptors recognise and respond to free fatty acids of varying chain length [1]. FFA2 and FFA3 respond to an overlapping group of short chain fatty acids produced largely by microbial fermentation of non-digestible carbohydrates in the gut. The C2 fatty acid acetate displays a degree of selectivity for human FFA2 over FFA3 and has been used, therefore, to predict specific roles for FFA2. However, this selectivity is not preserved for the rodent orthologues of these receptors, eliminating the usefulness of this ligand as a selective tool in rodent cells and tissues. A series of selective allosteric agonists of FFA2 have been described [2] and although of use, they may activate the receptor in a manner distinct from the endogenous orthosteric agonists. Bovine FFA2, but not FFA3, displays markedly different pharmacology than human and rodent FFA2, responding to fatty acids of substantially longer chain length. We used combinations of homology modelling and mutagenesis to define the basis for this difference and to engineer a form of human FFA2 with ‘bovine-like’ pharmacology that also fails to respond to C1-C4 fatty acids. A series of more potent and selective orthosteric FFA2 ligands have also recently become available and these are likely to provide novel insight into the specific roles of this receptor. FFA1 and GPR120, although only distantly related to each other, respond to a similar group of medium and longer chain free fatty acids [3]. Screening and medicinal chemistry programmes have resulted in the identification of moderately potent and selective FFA1 agonists and antagonists and such an agonist is currently undergoing late stage clinical trials to control hyperglycaemia [4]. Recently, a novel series of markedly selective agonists for GPR120 has also been described. Rapid progress in understanding the basis of fatty acid binding by these various G protein-coupled receptors [5] is resulting in the production and availability of a number of new selective pharmacological tools and these are likely to provide novel insights into the function of the individual receptors.