The major goals of this paper were: (i) to develop a computational model of the G2/M DNA damage checkpoint regulation; (ii) to uncover the effects of dynamic interactions between the cell cycle, Plk1, and p53 pathway regulators on the G2/M DNA damage checkpoint state; (iii) to explain Plk1-depletion-induced arrest and apoptosis in cancer cells; and (iv) to identify gene perturbations that induce a cell cycle arrest in different cancer cell lines. The gene discussed is PLK1; the disease is cancer.