E3 ligase mediated targeted protein degradation is an ever more important area in drug discovery. In the case of cereblon two avenues exist; either heterobifunctional PROTACs, or discrete cereblon ligands that induce a specific neosubstrate degron association to the complex. Here we present a degron blocking approach, whereby structural and in silico understandings of degron association has directed ligand design to block IMiD-like binding of degron containing neosubstrates, thus enhancing PROTAC selectivity. More information can be found in the Research Article by H. Bouguenina, J. J. Caldwell et al.