||Cell cycle is a unidirectional process that should be regulated tightly in order for parental cells to produce healthy daughter cells. One of the most critical criteria defining the health of daughter cells is the maintenance of genomic stability. In mammalian cell cycle, several checkpoints, when activated by the corresponding stimulus, are capable of blocking cell cycle progression, allowing the cell to have sufficient time to finish the previous phase before entering the next one. Conceptually, an intact checkpoint should include both the ability to arrest the cell cycle and to direct the cell to apoptosis when necessary. However, if every checkpoint works independently of each other, then the cell will not be able to maintain genomic stability when one of the checkpoints fails. In this study, I demonstrated that there is a second-line protection mechanism behind the basic requirements a cell cycle checkpoint should meet. The spindle-assembly checkpoint was essential for inducing mitotic cell death after the G2 DNA damage checkpoint was circumvented with the CHK1 inhibitor UCN-01. Disruption of the spindle-assembly checkpoint completely prevented mitotic cell death. Conversely, upregulation of the checkpoint enhanced mitotic cell death dramatically. The crosstalk between the DNA damage checkpoint and the spindle-assembly checkpoint ensures a high fidelity of checkpoint function in mammalian cells, thus safeguarding genomic stability. My results provide important insights on the design of chemotherapy targeting both the DNA damage checkpoint and spindle-assembly checkpoint simultaneously.