Structure-based drug design allows medicinal chemists to see, at atomic resolution, how a drug ligand binds to its target in three dimensions and has expedited the discovery of therapeutics against the most recalcitrant of drug targets. PROTACs, with their increased size and complexity, stand to equally gain from a structure-based design approach. While small molecules and PROTACs both require the design of ligands which bind potently, PROTAC design involves the additional step of stabilizing the interaction between two proteins, the E3-ligase and the protein of interest. This second protein–protein interaction stabilization step of PROTAC design is where PROTACs gain their potency and selectivity advantages over classical small molecules. It is the structural insights gained from the practice of structure-based PROTAC design which promises to accelerate the discovery of highly potent and selective PROTAC drugs.