The 5th US-EU Conference on Repair of Endogenous DNA Damage will focus on the DNA repair responses to naturally formed genomic damage, and the relationship of defects in these responses to genetically inherited disorders associated with cancer predisposition, neurological deficits and premature aging. Understanding the contributions of endogenous DNA damage to human disease, in particular cancer, and the pathological changes associated with aging remains the major theme of this conference. Recently, there has been an explosion of information about the incidence and spectra of mutations in cancer genomes. These studies have revealed an unexpectedly large number of base substitutions, many of which are likely to be driven by persistent endogenous DNA damage. A major goal of this meeting is to foster collaborative research on the cellular processes that affect this type of genomic instability in cancer. The role of endogenous DNA damage, in particular oxidative DNA damage, as a driver of normal and accelerated aging and the study of premature aging syndromes remain important areas of interest. Insights from rare inherited human diseases with defects in the DNA damage response continue to illuminate links between endogenous DNA damage and cancer, aging and neurologic disease. To promote the translation of knowledge about the sources and repair of endogenous DNA lesions into interventions that improve global human health, this meeting will stimulate collaborative translational research focused on the identification of new therapeutic targets and the development of treatment strategies that either regulate DNA repair pathways in order to enhance cancer treatment or delay neurodegeneration, or to reduce the pathological changes associated with aging.