Class B GPCRs comprise a family of receptors for a variety of therapeutically relevant peptide hormones. Their activity is implicated in several pivotal biological processes, including the regulation of blood glucose, growth, calcium homeostasis, neurotransmission, vasodilation and stress. All class B receptors possess a characteristic disulphide-linked extracellular domain (ECD) involved in hormone binding. Recent structural elucidations of class B GPCR ECDs in complex with their natural ligands or synthetic analogs reveal common modes of hormone recognition. A consensus is developing that ECD binding invokes α-helix formation of the hormone, which in turn leads to receptor activation. Progress in the structural determination of ECDs suggests that they are also directly involved in regulation of receptor activity.