Recent years have seen an unprecedented level of innovation in allosteric drug discovery and development, with multiple drug candidates advancing into clinical studies. From early examples of allosteric drugs like GABAA receptor modulators (benzodiazepines) in the 1960s to more recent GPCR negative allosteric modulators of CCR5 (maraviroc) approved in 2007, the opportunities for interrogating allosteric sites in drug discovery have expanded to other target classes such as protein-protein interactions, kinases, and nuclear hormone receptors. In this Innovation Letter, the authors highlight the latest advances of allosteric drug discovery from different target classes and novel emerging chemical modalities beyond small molecules.