In this study, through an unbiased DUBs-focused siRNA screen, we have identified USP13 as a novel MCL1 deubiquitinase that interacts with MCL1, reverses MCL1 ubiquitylation, protects MCL1 from proteasomal degradation and promotes tumor cell survival, particularly in the presence of extrinsic stresses, such as those generated by hypoxia, oxidants or pro-apoptotic BH3 mimetic inhibitors. Here, USP13 is linked to neoplasm.