Although a plurality of drugs target G-protein-coupled receptors (GPCRs), most have emerged from classical medicinal chemistry and pharmacology programs and resemble one another structurally and functionally. Though effective, these drugs are often promiscuous. With the realization that GPCRs signal via multiple pathways, and with the emergence of crystal structures for this family of proteins, there is an opportunity to target GPCRs with new chemotypes and confer new signaling modalities. We consider structure-based and physical screening methods that have led to the discovery of new reagents, focusing particularly on the former. We illustrate their use against previously untargeted or orphan GPCRs, against allosteric sites, and against classical orthosteric sites that selectively activate one downstream pathway over others. The ligands that emerge are often chemically novel, which can lead to new biological effects.