G protein-coupled receptors (GPCRs) are the largest class of membrane receptors in humans. As such, GPCR signaling is central to human biology and medicine. While more than 30% of approved drugs target roughly 150 GPCRs, most receptors lack well-defined endogenous ligands and are currently not druggable. To address this challenge, we created DCyFIR, a GPCR screening platform for ligand and drug discovery. This technology enables the cost-effective profiling of ligands and drug compounds against mixtures of hundreds of GPCR barcoded cell strains in a single experiment. Because ligands are tested against many receptors simultaneously, DCyFIR profiling will eventually enable the physical screening of huge numbers of compounds, bringing wet-laboratory experimental throughput a step closer to what is done in silico.