Lenalidomide, a thalidomide-like drug, targets Ikaros family zinc finger proteins (IKZF1 and IKZF3) through cereblon-dependent proteasomal degradation, contributing to its therapeutic effect in multiple myeloma. The study shows that lenalidomide binds to cereblon, a component of the ubiquitin ligase, and alters its substrate specificity to include IKZF1 and IKZF3. Loss of these proteins is necessary and sufficient for lenalidomide's therapeutic effect, suggesting that its antitumor and teratogenic activities are dissociable. Thalidomide was banned due to its teratogenic effects but has regained interest as an immunomodulator and antineoplastic agent. The study reveals that lenalidomide enhances the binding of IKZF1 and IKZF3 to cereblon, leading to their ubiquitylation and degradation. This mechanism is specific to IKZF1 and IKZF3, as lenalidomide does not affect other Ikaros family members. The findings indicate that lenalidomide's antimyeloma activity is linked to the down-regulation of IKZF1 and IKZF3, which are critical for B cell development and are highly expressed in B cell malignancies. The study also shows that lenalidomide resistance can be overcome by stabilizing IKZF1 or IKZF3, suggesting that these proteins are important targets for lenalidomide's action. The results highlight the potential of targeting cereblon and its substrates for the treatment of myeloma and other B cell malignancies.Lenalidomide, a thalidomide-like drug, targets Ikaros family zinc finger proteins (IKZF1 and IKZF3) through cereblon-dependent proteasomal degradation, contributing to its therapeutic effect in multiple myeloma. The study shows that lenalidomide binds to cereblon, a component of the ubiquitin ligase, and alters its substrate specificity to include IKZF1 and IKZF3. Loss of these proteins is necessary and sufficient for lenalidomide's therapeutic effect, suggesting that its antitumor and teratogenic activities are dissociable. Thalidomide was banned due to its teratogenic effects but has regained interest as an immunomodulator and antineoplastic agent. The study reveals that lenalidomide enhances the binding of IKZF1 and IKZF3 to cereblon, leading to their ubiquitylation and degradation. This mechanism is specific to IKZF1 and IKZF3, as lenalidomide does not affect other Ikaros family members. The findings indicate that lenalidomide's antimyeloma activity is linked to the down-regulation of IKZF1 and IKZF3, which are critical for B cell development and are highly expressed in B cell malignancies. The study also shows that lenalidomide resistance can be overcome by stabilizing IKZF1 or IKZF3, suggesting that these proteins are important targets for lenalidomide's action. The results highlight the potential of targeting cereblon and its substrates for the treatment of myeloma and other B cell malignancies.