G protein-coupled receptors (GPCRs) mediate a wide range of signalling processes and are targeted by one third of the drugs in clinical use 1. Although most GPCR-targeting therapeutics are small molecules 2 , the endogenous ligands for many GPCRs are peptides (comprising 50 or fewer amino acids), which suggests that this class of molecule could be therapeutically useful. GPCRs are divided into families based on structural similarities. The largest group is the class A (rhodopsinlike) family, followed by the class B (secretin) family. Although other families exist, including class C and the frizzled and adhesion classes, therapeutics have predominantly targeted class A and B GPCRs, so this Review is focused on these two groups. The International Union of Basic and Clinical Pharmacology (IUPHAR) Guide to Pharmacology 3 currently lists 197 class A receptors with known ligands (excluding olfactory, vision, taste and vomeronasal sensory receptors), where 64 (32%) of these bind to endogenous peptides 3. In GPCR class B, there are 20 receptors activated by 15 endogenous peptides. These GPCRs are grouped in the following families, based on the ligand to which they bind: calcitonin, corticotropin-releasing factor, glucagon, parathyroid hormone (which is generally considered to be a peptide, despite its 84-amino-acid length), vasoactive intestinal peptide (VIP) or pituitary adenylate cyclase-activating peptide (PACAP).