G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and are important human drug targets. Of the 826 human GPCRs, 118 of them recognize endogenous peptide or protein ligands, and 30 of the 118 are targeted by approved drug molecules, including the very high-profile class B glucagon-like peptide 1 receptor. In this review, we analyze the 21 experimentally determined three-dimensional structures of the known peptide-binding GPCRs in relation to the endogenous peptides and drug molecules that modulate their cell signaling processes. Our integrated analyses reveal that half of the marketed drugs and most of the drugs in clinical trials that interact with peptide GPCRs are small molecules with a wide range of binding modes distinct from those of large peptide ligands. As we continue to collect additional data on these receptors from orthogonal approaches, including nuclear magnetic resonance and electron microscopy, we are beginning to understand how these receptors interact with their ligands at the molecular level and how improving the pharmacology of GPCR signal transduction requires us to study these receptors using multiple biophysical techniques.