Abstract In response to DNA damage a cell can be forced to permanently exit the cell cycle and become senescent. Senescence provides an early barrier against tumor development by preventing proliferation of cells with damaged DNA. By studying single cells, we show that Cdk activity is retained after DNA damage until terminal cell cycle exit. The low level of Cdk activity not only allows cell cycle progression, but also forces cell cycle exit at a decision point in G2 phase. We find that Cdk activity stimulates p21 production, leading to nuclear sequestration of Cyclin B1, subsequent APC/C Cdh1 -dependent degradation of mitotic inducers and induction of senescence. We suggest that the same activity that triggers mitosis in an unperturbed cell cycle drives senescence in the presence of DNA damage, ensuring a robust response when most needed.