Although the human genome encodes over 600 E3 ligases, very few of them ((VHL, CRBN, IAP, MDM2) have been used to trigger small-molecule-induced degradation. Since different ligases show specificity for recruitment and degradation of unique target proteins, it is believed possible to expand the reach of molecular glue degraders and eliminate so far undruggable proteins by accurately selecting new E3 ligases as targets for drug discovery. Moving beyond the most widely employed cereblon E3 ligase will therefore significantly expand the therapeutic capacity of induced protein degradation.