Molecular glue degraders (MGDs) induce degradation of non-native protein substrates (neo-substrates) through the E3 ubiquitin ligase CRL4CRBN. MGD discovery is largely serendipitous, and the specificity of MGD-mediated target selection remains poorly understood. We developed an MGD discovery pipeline to identify cereblon (CRBN)–MGD neo-substrates and structural determinants of MGD-mediated degradation.