An underlying hallmark of cancers is genomic instability and a greater propensity to accumulate DNA damage. Historical cancer therapy by radiotherapy and DNA-damaging chemotherapy is based on this principle but is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions.