Immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch DNA recombination (CSR) are critical for the maturation of the antibody response. These processes endow antibodies with increased antigen-binding affinity and acquisition of new biological effector functions, thereby underlying the generation of memory B cells and plasma cells. They are dependent on the generation of specific DNA lesions and the intervention of activation-induced cytidine deaminase as well as newly identified translesion DNA polymerases, which are expressed in germinal center B cells. DNA lesions include mismatches, abasic sites, nicks, single-strand breaks, and double-strand breaks (DSBs). DSBs in the switch (S) region DNA are critical for CSR, but they also occur in V(D)J regions and possibly contribute to the events that lead to SHM. The nature of the DSBs in the Ig locus, their generation, and the repair processes that they trigger and that are responsible for their regulation remain poorly understood. Aberrant regulation of these events can result in chromosomal breaks and translocations, which are significant steps in B-cell neoplastic transformation.