The impact of DNA damage on cell cycle progression is cell cycle stage dependent. In mitosis, DNA damage induces mitotic catastrophe which is manifested as either cell death or failure of cytokinesis. The latter leads to the formation of binucleated cells and cell cycle arrest in Gl state via the p53-dependent tetraploid checkpoint. It is not clear whether the failure of cytokinesis is a result of mechanical problems associated with the damaged DNA or is a regulated process. Recently, we discovered the presence of a mitotic exit DNA damage checkpoint in mammalian cells that prevents cytokinesis. We propose that this checkpoint is responsible for mitotic catastrophe and functions as the last line of defense in preserving genome stability. We will identify mechanisms used by the checkpoint to stop mitosis and to induce mitotic catastrophe, and will determine the physiological significance of this checkpoint.