AbstractA 29‐amino acid polypeptide hormone, glucagon has been one of the most prolific models in the study of hormone action. The key biologic function of glucagon is to counterbalance the actions of insulin and maintain a normal level of serum glucose. Diabetes mellitus can thus be considered a bihormonal disorder with an excess of glucagon contributing to the hyperglycemic state. The effects of glucagon are mediated by the glucagon receptor, which is itself a prototypical member of a distinct category called family B receptors within the G protein‐coupled superfamily of seven‐helical transmembrane receptors (GPCRs). At the structural level, the peptide ligands of family B receptors are highly homologous, in particular in the N‐terminal region of the molecules. The mechanism by which highly homologous peptide ligands selectively recognize their receptors involves distinct molecular interactions that are gradually being elucidated. This review focuses on structural determinants of the glucagon receptor that are important for its activity with respect to interaction with its ligand and G proteins. Information about the glucagon receptor is presented within the context of what is known about other members of the family B GPCRs. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 218–235, 2002