This study describes significant improvements to the proteolysis-targeting chimeras (PROTACs) method, a chemical approach for protein knockdown. PROTACs are heterobifunctional molecules that recruit a specific protein target to an E3 ubiquitin ligase, leading to the target's ubiquitination and degradation. The authors present two PROTACs that can reduce protein levels by over 90% at nanomolar concentrations. These compounds exhibit catalytic activity, inducing ubiquitination of super-stoichiometric quantities of proteins, and do not rely on equilibrium occupancy. In vitro and in vivo studies demonstrate that these PROTACs are highly selective and effective, with broad tissue distribution and potent protein knockdown in tumor xenografts. This work highlights the potential of PROTACs as a powerful tool for achieving potent and selective protein knockdown, combining the advantages of small-molecule agents with the efficacy of RNAi and CRISPR/Cas9 technologies.This study describes significant improvements to the proteolysis-targeting chimeras (PROTACs) method, a chemical approach for protein knockdown. PROTACs are heterobifunctional molecules that recruit a specific protein target to an E3 ubiquitin ligase, leading to the target's ubiquitination and degradation. The authors present two PROTACs that can reduce protein levels by over 90% at nanomolar concentrations. These compounds exhibit catalytic activity, inducing ubiquitination of super-stoichiometric quantities of proteins, and do not rely on equilibrium occupancy. In vitro and in vivo studies demonstrate that these PROTACs are highly selective and effective, with broad tissue distribution and potent protein knockdown in tumor xenografts. This work highlights the potential of PROTACs as a powerful tool for achieving potent and selective protein knockdown, combining the advantages of small-molecule agents with the efficacy of RNAi and CRISPR/Cas9 technologies.