It has long been appreciated that free fatty acids can serve as metabolic substrates in the pancreatic β-cell and that they are able to regulate the secretory activity of these cells by coordinating the oxidation of relevant fuel molecules within the mitochondria [1]. It has also been proposed that fatty acids can propagate intracellular signalling by, for example, altering the formation of acyl-CoA species within β-cells or by modulating the availability of eicosanoids and/or other metabolites [1,2]. In addition, excessively high concentrations of free fatty acids are known to exert detrimental effects on β-cells in that they cause both a loss of glucose-induced insulin secretion and a subsequent decline in cell viability [3]. As such, it has widely been argued that elevated levels of circulating free fatty acids may contribute to the decline in glucose homeostasis seen in patients with type 2 diabetes. Until recently, it was considered likely that fatty acids exert the majority of their actions upon entry into the β-cell. However, it is now clear that they can also influence cell function by acting more directly from the extracellular environment. This is because β-cells express various members of a family of G-protein coupled receptors that can bind fatty acids in the extracellular space and which transmit signals to the intracellular environment [4]. These molecules were originally identified as orphan receptors but it is now established that their endogenous ligands are either free fatty acids per se or, in some cases, fatty acid derivatives. Such receptors are implicated in mediating at least part of the stimulatory actions of free fatty acids on insulin secretion and they have also been proposed as mediators of altered β-cell viability in type 2 diabetes. Among this family of receptors, those members which have received most attention in relation to their ability to control β-cell function are FFA1 (formerly GPR40) and GPR119, although more recent work has also begun to focus on GPR120. Both FFA1 and GPR119 play a role in the early potentiation of glucose-induced insulin secretion by exogenous free fatty acids and each is expressed in the β-cell. By contrast, the role of GPR120 is more controversial and uncertainties remain about the role and expression of this molecule in β-cells. From a therapeutic perspective, the finding that FFA1 and GPR119 can each enhance glucose-induced insulin secretion, has prompted a range of investigators to develop selective agonists that might be useful as modulators of β-cell secretory activity in vivo. However, it is also possible that such molecules might exert a second beneficial effect by preserving β-cell viability in an analogous manner to that proposed for agonists of a different GPCR, the GLP-1 receptor. In this case, it is well established that addition of GLP-1 leads to a potentiation of glucose-induced insulin secretion but there is also evidence that activation of the GLP-1 receptor may lead to a cytoprotective response in β-cells [5]. Therefore, it is of interest to establish whether a similar process may ensue following activation of relevant free fatty acid receptors in β-cells. To address this issue, we have studied, in more detail, the possibility that GPR119 might mediate a cytoprotective action in β-cells using a putative endogenous ligand for this receptor, oleoylethanolamide (OEA) [6]. Treatment of cultured pancreatic β-cells with exogenous palmitate (C16:0) led to a dose-dependent loss of viability during periods of >24h and this response was attenuated very effectively by co-incubation with various mono-unsaturated fatty acids, including oleate (C18:1). Oleate alone was well-tolerated by the cells. Like oleate, OEA, also failed to exert any obvious cytotoxic actions in rodent β-cells but it dramatically attenuated the loss of viability caused by palmitate and was apparently more potent than oleate. The response to OEA was not reproduced by any of several synthetic agonists of GPR119 and, more surprisingly, it was abrogated by inclusion of inhibitors of fatty acid amide hydrolase (FAAH). Taken together, the data imply that OEA is not, itself, the active cytoprotective species but that it is rapidly converted to free oleate (by the action of FAAH) which then mediates cytoprotection. This, in turn, implies that the cytoprotective response is unlikely to be mediated by GPR119. Indeed, it seems probable that oleate mediates this effect from an intracellular site rather than via a cell surface receptor.