DNA damage evokes a complex array of cellular responses, including cycle arrest in late G1 and/or G2 phases, and delayed progression through S phase. Arrest at these points in the cell cycle is governed, in large part, by a series of control systems, commonly termed "checkpoints". Activation of these checkpoints tends to protect cells from DNA damage by providing cells additional time to complete DNA repair. We discuss the impact of these DNA damage checkpoints on the chemosensitivity of human cancer cells. We focus on some of the complexities of the p53-dependent G1 checkpoint and review some recently discovered vulnerabilities in p53 disrupted cells that might be pharmacologically exploited for cancer treatment.