This study explores the use of DCAF1, an essential E3 ligase receptor, as a target for targeted protein degradation (TPD) using non-covalent binders. The authors developed a selective, non-covalent DCAF1 binder and validated its functionality as an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments confirmed specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degraded cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) was shown to degrade BTK in cells with acquired resistance to CRBN-BTK-PROTACs, highlighting DCAF1-PROTACs as a promising strategy to overcome ligase-mediated resistance in clinical settings. The study also demonstrated that DCAF1-PROTACs can be used as an alternative to VHL-based degraders in cells lacking VHL expression or with acquired resistance to CRBN-based degraders.This study explores the use of DCAF1, an essential E3 ligase receptor, as a target for targeted protein degradation (TPD) using non-covalent binders. The authors developed a selective, non-covalent DCAF1 binder and validated its functionality as an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments confirmed specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degraded cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) was shown to degrade BTK in cells with acquired resistance to CRBN-BTK-PROTACs, highlighting DCAF1-PROTACs as a promising strategy to overcome ligase-mediated resistance in clinical settings. The study also demonstrated that DCAF1-PROTACs can be used as an alternative to VHL-based degraders in cells lacking VHL expression or with acquired resistance to CRBN-based degraders.