Cancer cells experience high levels of replication stress and have therefore adapted mechanisms to tolerate replication stress. Using a CRISPR screen, we identified RNF25 as a mediator of replication stress tolerance in cancer cells. RNF25-ablation results in ssDNA accumulation, decreased replication fork movement, and increased replication fork degradation dependent on nucleases MRE11 and CtIP. To identify potential interactors of RNF25 in mediating replication stress tolerance, we performed mass-spectrometry analysis of immunopurified RNF25-complexes. We discovered REV7 as a novel binding partner of RNF25. REV7 was previously shown to protect replication forks in a Shieldin-independent but REV1- and REV3L-dependent manner. Further investigation revealed that RNF25 is also epistatic to REV1 and REV3L in a fork protection pathway and that REV7 recruitment to replication forks following stress is dependent on RNF25. Our findings establish a novel role of RNF25 in replication fork protection.