Whole chromosomal instability (CIN) is known to contribute to aneuploidy, but can it also cause DNA damage? In cells in which aneuploidy is promoted by a drug that induces incorrect kinetochore attachment, and hence lagging chromosomes at mitosis, sites of DNA damage and chromosomal rearrangements are increased. Chromosomes that are incorrectly segregated are often damaged during cytokinesis, and the resulting DNA double-strand breaks trigger an ataxia telangiectasia mutated (ATM)–CHK2–p53-mediated DNA damage response. These data further imply that CIN actively contributes to genomic instability and potentially to a tumorigenic phenotype.