The fallopian tube precursor lesion for high-grade serous ovarian cancer is characterized by chromosomal instability and a high level of aneuploidy. Treatment of fallopian tube epithelial cells with inhibitors to Mps1 and CENP-E induces chromosomal instability and formation of "atypical mitoses," characterized by multipolar spindles, polar chromosomes, and lagging chromosomes during anaphase. The aneuploid post-mitotic cells incur proteotoxic stress and acquire sensitivity to proteasome inhibition. For details, see the article by Chui and colleagues on page 5536.