Cancer drug resistance has become the major problem facing current clinical treatment via different kinds of therapies. Proteolysis targeting chimeras (PROTACs) as a novel and powerful strategy have attracted a great deal of attention both from academia and from industry for their sensitivity to drug-resistant targets relying on their unique characteristics compared to those of traditional inhibitors. PROTACs exert their function by degrading the target protein instead of inhibiting targets. Thus, different kinds of resistance could be conquered by PROTACs such as target mutation or overexpression. Various resistant targets have been overcome by PROTACs, including AR, ER, BTK, BET, and BCR-ABL. Though PROTACs have achieved some significant advances in combating drug resistance, more cases are needed to prove the efficiency of PROTACs in addressing the hurdle of resistance in the near future.