The mitotic checkpoint plays an important role in preventing chromosome segregation errors and the production of aneuploid progeny. In this issue, Zhang et al. examine mice and cells lacking the deubiquitinating enzyme USP44. Surprisingly, they find that USP44 prevents chromosome segregation errors through a function independent of its previously identified role in the mitotic checkpoint. Usp44-null animals develop aneuploidy and experience increased rates of tumorigenesis, implicating USP44 as novel tumor suppressor.