Illuminating the understudied GPCR-ome

•GPCRs are targets of 30–40% of approved drugs.•There exist ∼100 orphan or understudied GPCRs which represent targets for new drug development.•Computational and structural approaches are accelerating the discovery of novel drugs for understudied GPCRS. G-protein-coupled receptors (GPCRs) are the target of >30% of approved drugs. Despite their popularity, many of the >800 human GPCRs remain understudied. The Illuminating the Druggable Genome (IDG) project has generated many tools leading to important insights into the function and druggability of these so-called ‘dark’ receptors. These tools include assays, such as PRESTO-TANGO and TRUPATH, billions of small molecules made available via the ZINC virtual library, solved orphan GPCR structures, GPCR knock-in mice, and more. Together, these tools are illuminating the remaining ‘dark’ GPCRs.