Our genetic material (DNA) is continually subjected to damage, either from endogenous cellular sources such as reactive oxygen species that arise as by-products of oxidative metabolism, from the breakdown of replication forks during cell growth, or by agents in the environment such as ionizing radiation or carcinogenic chemicals. To cope with such damage, cells employ a variety of processes that recognize and repair lesions in DNA. These repair systems are essential for the maintenance of genome integrity and for cancer avoidance.The focus of our research over the past 40 years has been to determine the cellular mechanisms for repair — in particular DNA double-strand break repair — and to determine why defects in these processes lead to inheritable cancers. Chromosome breakage is a characteristic phenotype of individuals with inheritable breast cancers caused by mutation of the BRCA2 gene, acute leukemias associated with Fanconi anemia, and a wide range of cancers found in individuals with the chromosome instability disorder known as Bloom’s syndrome. Over the years, many of the proteins required for DNA break repair have been purified in our laboratory, and we have used biochemical, structural, and molecular and cell biological approaches to understand how they promote genome stability and thereby avoid tumourigenesis.