Human chromosomes are constantly assaulted by challenges to their integrity as a result of either environmental agents that damage DNA or from normal DNA metabolism. The failure to repair damaged DNA faithfully is ultimately responsible for many human diseases, especially cancer. This laboratory focuses on the repair of 1 particular lesion in DNA, the double-strand break (DSB). DSBs arise from agents, such as ionizing radiation, and can also occur spontaneously during DNA replication. Our emphasis is on repair of DSBs by homologous recombination, with a particular interest in the role of homologous recombination in maintaining genetic stability. Understanding the repair of DSBs is not only important for basic science and health concerns, but also impacts on molecular genetic manipulations of mammalian genomes.