DNA-damaging therapies represent the most frequently used non-surgical anticancer strategies in the treatment of human tumors. These therapies can kill tumor cells, but at the same time they can be particularly damaging and mutagenic to healthy tissues. The efficacy of DNA-damaging treatments can be improved if tumor cell death is selectively enhanced, and the recent application of poly-(ADP-ribose) polymerase inhibitors in BRCA1/2-deficient tumors is a successful example of this. DNA damage is known to trigger cell-cycle arrest through activation of DNA-damage checkpoints. This arrest can be reversed once the damage has been repaired, but irreparable damage can promote apoptosis or senescence. Alternatively, cells can reenter the cell cycle before repair has been completed, giving rise to mutations. In this review we discuss the mechanisms involved in the activation and inactivation of DNA-damage checkpoints, and how the transition from arrest and cell-cycle re-entry is controlled. In addition, we discuss recent attempts to target the checkpoint in anticancer strategies.