G protein-coupled receptors (GPCRs) are the largest family of cell signaling transmembrane proteins that can be modulated by a plethora of chemical compounds. Systematic cheminformatics analysis of structurally and pharmacologically characterized GPCR ligands shows that cocrystallized GPCR ligands cover a significant part of chemical ligand space, despite their limited number. Many GPCR ligands and substructures interact with multiple receptors, providing a basis for polypharmacological ligand design. Experimentally determined GPCR structures represent a variety of binding sites and receptor–ligand interactions that can be translated to chemically similar ligands for which structural data are lacking. This integration of structural, pharmacological, and chemical information on GPCR–ligand interactions enables the extension of the structural GPCR–ligand interactome and the structure-based design of novel modulators of GPCR function.