This study presents the development of DCAF1-based PROTACs that effectively target clinically relevant proteins, overcoming both intrinsic and acquired resistance to degraders. DCAF1, an essential E3 ligase receptor, was utilized with a selective, non-covalent binder to enable targeted protein degradation (TPD). The DCAF1-BRD9 PROTAC (DBr-1) and DCAF1-BTK PROTAC (DBt-10) were developed and validated for their ability to degrade BRD9 and BTK, respectively. DBr-1 demonstrated potent degradation of BRD9 with sub-μM potency, while DBt-10 showed effective degradation of BTK in cells resistant to CRBN-based degraders. These PROTACs were shown to be effective in cellular models and were validated through chemical and genetic rescue experiments. The study also highlights the potential of DCAF1 as an alternative E3 ligase for TPD, particularly in cases where VHL or CRBN-based degraders are ineffective due to resistance mechanisms. The results demonstrate that DCAF1-based PROTACs can overcome resistance by targeting essential E3 ligases, offering a promising strategy for overcoming ligase-mediated resistance in clinical settings. The study provides a comprehensive characterization of DCAF1-based PROTACs, including their binding affinity, degradation efficiency, and selectivity, and highlights their potential as next-generation degraders for therapeutic applications.This study presents the development of DCAF1-based PROTACs that effectively target clinically relevant proteins, overcoming both intrinsic and acquired resistance to degraders. DCAF1, an essential E3 ligase receptor, was utilized with a selective, non-covalent binder to enable targeted protein degradation (TPD). The DCAF1-BRD9 PROTAC (DBr-1) and DCAF1-BTK PROTAC (DBt-10) were developed and validated for their ability to degrade BRD9 and BTK, respectively. DBr-1 demonstrated potent degradation of BRD9 with sub-μM potency, while DBt-10 showed effective degradation of BTK in cells resistant to CRBN-based degraders. These PROTACs were shown to be effective in cellular models and were validated through chemical and genetic rescue experiments. The study also highlights the potential of DCAF1 as an alternative E3 ligase for TPD, particularly in cases where VHL or CRBN-based degraders are ineffective due to resistance mechanisms. The results demonstrate that DCAF1-based PROTACs can overcome resistance by targeting essential E3 ligases, offering a promising strategy for overcoming ligase-mediated resistance in clinical settings. The study provides a comprehensive characterization of DCAF1-based PROTACs, including their binding affinity, degradation efficiency, and selectivity, and highlights their potential as next-generation degraders for therapeutic applications.