We use molecular, cellular, genomics, proteomics and systems biology approaches to study the fundamental mechanisms that control the cellular response to DNA damaging agents. These regulatory events are central to two of the major issues in the field of cancer biology: 1) how and when cancers start and progress; and 2) what determines the sensitivity of tumors to therapeutic interventions. In terms of cancer causation, the critical role for the DNA damage response is demonstrated by the fact that a number of human cancer susceptibility syndromes are caused by inherited mutations affecting the DNA damage response. For example, inherited mutations in damage-response genes can lead to skin cancers (xeroderma pigmentosum genes), leukemia and lymphoma (ATM, NBS1 and Fanconi anemia genes), breast and ovarian cancers (p53, BRCA1, BRCA2), colon cancers (mismatch repair genes), and brain tumors (p53). The epidemiological observation that exposure to environmental DNA damaging agents contributes to at least 80 percent of all human cancers further illustrates the importance of these damage responses in cancer causation. On the other hand, since many cancer therapeutic interventions attempt to kill tumors by targeting the DNA, gene products involved in DNA damage-response pathways are also predictably critical for determining therapeutic outcomes. Thus, elucidation of the mechanisms involved in the DNA damage response has obvious importance both for understanding cancer causation and for eliciting cancer cures.