Maintaining the stability of the genome is critical to normal cell growth and development. The early notion that cancer is the result of mutations in genes controlling cellular growth implied that gene or genome integrity is vital to the prevention of oncogenesis, and many genes and pathways that prevent genomic deterioration have been identified over the past decades. Recent progress in reverse genetic approaches, principally RNA interference, now allows the systematic analysis of gene function on a genomic scale in an animal system. Here, we discuss genomic approaches in the model organism Caenorhabditis elegans, aimed to identify genes and genetic networks that contribute to genome stability and are thus potentially involved in human carcinogenesis.