The DNA of all cells is continually under assault from a wide range of DNA-damaging agents. To counter this threat to their genetic integrity, cells possess systems, collectively known as the DDR (DNA-damage response), to detect DNA damage, signal its presence and mediate its repair. In the present article, I provide an overview of the DDR and then describe how work in my laboratory and elsewhere has identified some of the key protein players that mediate cellular responses to the most cytotoxic form of DNA damage: the DNA DSB (double-strand break). I also discuss some of my laboratory's recent work, which has revealed that the way cells respond to DSBs is modulated in a cell-cycle-dependent manner to ensure that the cell uses the DSB repair system that is most suited to its cell-cycle stage. Finally, I explain how our increasing knowledge of the DDR is suggesting new avenues for treating cancer and provide an example of a DDR-inhibitory drug that is showing promise in clinical trials.