Protection from cancer and ensured longevity are tightly linked in mammals. One of the fundamental mechanisms contributing to both is the cellular response to DNA damage. The appropriate response is an initial attempt at repair, but if the damage is too extensive or compromises DNA metabolism, a signalling cascade triggers cellular senescence or death. Evidence in mice and humans suggests a division of tasks amongst DNA repair pathways: transcription-coupled repair and interstrand crosslink repair of cytotoxic lesions are predominantly responsible for longevity assurance, whereas excision repair of mutagenic lesions provides protection against cancer. Similarly, the signalling component of the DNA-damage response might contribute unequally to organismal outcomes depending on its set point: an inadequate response to DNA damage sanctions carcinogenesis but might limit local ageing, whereas overzealous signalling provides cancer protection but accelerates ageing.