G protein-coupled receptors (GPCRs) play a crucial role in cell signal transduction and comprise the largest drug target protein family. Despite recent breakthroughs in structural and pharmacological studies of these receptors, more than 100 GPCRs remain orphan receptors, i.e., their ligands and signaling pathways are unknown. This limits full understanding of the physiological functions and signaling mechanisms of the GPCR superfamily. As a "virgin land" of drug discovery, orphan receptors thus offer new opportunities for drug development by serving as potential drug targets.