Some of the most effective anticancer treatments in clinical use induce DNA damage. The majority of treatments cause severe side effects because they do not specifically target cancer cells but also affect other proliferating cells. Detection of genomic lesions activates the DNA damage response, which determines cell fate according to the extent of damage. If the damage is manageable, the DNA damage response arrests cell cycle progression and induces DNA repair to prevent replication of damaged DNA. If the damage is beyond repair, cells undergo apoptosis. Recently we have shown that the DNA damage response also alerts the innate immune system by inducing the expression of ligands for the activating immune receptor NKG2D. The potential of cancer drugs that target components of the DNA damage response and therapeutic hypotheses to improve current cancer therapies are discussed.