The immune system is the site of intense DNA damage/modification, which occur during the development and maturation of B and T lymphocytes. V (D) J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the non-homologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V (D) J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V (D) J recombination, requires the major factors of the DNA damage response. V (D) J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways.