There is currently significant attention surrounding glucose-lowering drugs based on incretins, a group of hormones released from the intestine that play a vital role in regulating whole-body glucose metabolism. Exendin-4, a peptide constituent of the venom of the Gila Monster first isolated in the 1990s, is structurally similar to the incretin hormone glucagon-like peptide-1 (GLP-1) and has been found to stimulate insulin secretion, suppress glucagon release and enhance satiety. These potentially beneficial effects for whole-body glucose metabolism and the realisation that exendin-4 could be used as a basis for the development of GLP-1 receptor agonists (GLP-1RAs) fuelled interest to develop incretin-based therapies in type 2 diabetes. The following decades have heralded novel insights into the biology of incretins and generated several glucose-lowering drugs. In this special issue we summarise the state-of-the-art knowledge about incretins, from basic biology and treatment modalities to socioeconomic aspects of novel therapies.