Significant progress has been made in recent years elucidating the molecular controls of cellular responses to DNA damage in mammalian cells. Many of the insights that we have gained into the mechanisms involved in cellular DNA damage response pathways have come from studies of human cancer susceptibility syndromes that are altered in DNA damage responses. ATM, the gene mutated in the cancer-prone disorder, ataxia telangiectasia, is a protein kinase that is a central mediator of responses to DNA double strand breaks in cells. Such insights provide us with opportunities to develop new approaches to benefit patients. For example, inhibitors of the ATM pathway have the potential to act as sensitizers to chemotherapy or radiation therapy and could even have anti-neoplastic effects on their own. Conversely, activators of ATM could improve responses to cellular stresses such as oxidative damage. The potential benefits of ATM modulation in disease settings ranging from metabolic syndrome to cancer will be discussed.