Defects in chromosome segregation during mitosis can result in aneuploidy and chromosome instability, which are associated with cancer. The propagation of chromosome abnormalities is restricted by the induction of cell death in cells that fail to complete chromosome segregation during mitosis. The propensity of a cell to undergo mitotic cell death is determined by the mitotic or spindle assembly checkpoint, which controls progression through mitosis, and by mitosis-specific regulation of the apoptotic pathway. Mitotic cell death is promoted by cancer chemotherapeutic drugs that arrest cells in mitosis or provoke DNA damage responses. We show that mitotic cell death is under the control of the products of oncogenes and tumour suppressors, and is linked to the progression of mitosis through protein phosphorylation and protein degradation. A key regulator of mitotic cell death is the anti-apoptotic oncoprotein Mcl-1, which is phosphorylated and slowly degraded during mitosis, providing a molecular timer that initiates cell death after a prolonged mitotic arrest. Cells arrested in mitosis that do not undergo full apoptosis still exhibit stress responses including a DNA damage response initiated at telomeres that that determines subsequent cell fate, including control of cell cycle progression and post-mitotic cell death. These mechanisms provide opportunities to enhance the response of cancer cells to chemotherapy and to develop new strategies for treating cancer.