The ability of eukaryotic cells to repair DNA double strand breaks (DSBs) is critical for the maintenance of genomic integrity. Unrepaired DNA breaks can lead to cell death, whereas improperly repaired breaks can lead to chromosomal rearrangements. Nonhomologous end joining (NHEJ) is one of two major evolutionarily conserved mechanisms for DSB repair. In addition to its role as a general DNA repair mechanism, NHEJ is responsible for the end joining reactions associated with V(D)J recombination in developing B and T lymphocytes. Errors in V(D)J recombination may lead to specific oncogenic chromosomal translocations, contributing to the development of neoplasms of B and T cell origin. Excision of the hobo transposable element of Drosophila melanogaster generates DSBs which appear to be repaired much like the DNA ends generated by V(D)J recombination. Experiments are proposed to analyze the intermediates and products of hobo excision in Drosophila cell culture, and to use RNA interference (RNAi) to identify protein factors required for NHEJ in Drosophila. The identification of new proteins required for NHEJ would lead to a better understanding of the molecular basis of cancer.