In summary, we report novel heterotrivalent dual ligase recruiting PROTACs that potently and rapidly degrade the engaged target protein. Trivalent CRBN-VHL-BET PROTAC AB3067 ( ) qualified as the most potent and fastest degrader, and most cytotoxic in BET sensitive cells. AB3067-induced BRD4 degradation was shown to be a result of ternary complexes with VHL and CRBN, and ubiquitination by each E3, suggesting that both E3 ligases are contributing to its activity. This is consistent with the evidence that loss of AB3067 cellular activity requires simultaneous loss of both recruited E3 ligases. We further exemplify a heterotetravalent PROTAC bearing a further copy of the BET ligand, and a heterotrivalent PROTAC with much improved degradation potency for BromoTag. Altogether, our work suggests that increasing valency to recruit two E3 ligases by the same PROTAC molecule can be an attractive strategy to augment the efficacy of targeted protein degradation. This approach could offer an opportunity to delay or overcome resistance to PROTAC degraders. Future work will be directed at exploring this important concept in cancer cells.