Class B G protein-coupled receptors (GPCRs) regulate a wide range of endocrine and neuroendocrine functions and are endogenously stimulated by moderately large peptide hormones. Current evidence suggests that the carboxyl termini of cognate peptides bind to the amino terminus of their G protein-coupled receptors (GPCRs) and that the peptides' amino terminal segments then dock to the heptahelical receptor portion to induce signaling. In this issue of Molecular Pharmacology, Dong et al. (p. 206) propose an alternative model of ligand-induced class B GPCR activation. Based primarily on studies with the secretin receptor, a prototype class B family member, they provide evidence that the endogenous peptide hormone does not function as an activator per se. Instead, this hormone (secretin) exposes a hidden, built-in agonist epitope that is present within the amino terminus of its target GPCR. Isolated oligopeptide fragments containing this epitope act as full agonists on the secretin receptor despite their lack of amino acid homology with the secretin hormone. These nonconventional agonists can be minimized to tripeptide molecules and still maintain biological activity. The study to be discussed introduces a novel paradigm of class B GPCR function, and may facilitate the elusive goal of finding small molecule agonist drugs for this therapeutically attractive group of receptors.