(TCR) specificities expressed on individual B and T lymphocytes. Antigen receptor diversity is created by the assembly of variable region gene segments by a process of somatic DNA rearrangement known as V (D) J recombination. Additional genetic alterations in Ig genes occur during immune responses through isotype class switch recombination and somatic hypermutation of variable regions in germinal center B cells. Thus, lymphocytes breach genomic integrity at several developmental stages to expand the germline genetic program. A central feature of neoplasms in the lymphoid lineage is chromosomal translocations, which occur in the majority of non-Hodgkin’s lymphomas (NHL) as well as in many acute leukemias and plasma cell neoplasms. Translocations in NHL characteristically juxtapose a cellular proto-oncogene with one of the antigen receptor loci, leading to deregulated oncogene expression. It has been hypothesized that such oncogenic translocations arise as byproducts of physiologic gene rearrangement processes, although evidence to date has been mostly circumstantial. In recent years, there have been important advances in several areas that make it appropriate to re-examine the connection between genetic instability at the antigen receptor loci and the pathogenesis of lymphoid malignancies. An understanding of the major steps of V (D) J recombination at both the genetic and biochemical levels has emerged, suggesting ways in which the recombinase mechanism may protect broken DNA ends from exposure to inappropriate repair mechanisms. It is now apparent that genetic plasticity in lymphocytes, especially involving the Ig loci in B cells, is much greater than previously appreciated. In particular, B-lineage cells are now known to undergo V (D) J recombination and revise Ig locus variable regions in response to antigenic stimulation. Germinal center B cells also undergo somatic hypermutation of Ig genes, a process that is now understood to involve DNA strand breaks, as well as Ig isotype switch recombination. Inasmuch as the most common types of nodal B-cell NHL are postulated to arise in the germinal center, these recent insights suggest that genomic instability that occurs in the context of immune responses may contribute to the genetic alterations leading to lymphoid neoplasia. Given the vigor with which chromosomal DNA is broken and repaired in lymphocytes during lineage development and antigen responses, it is perhaps appropriate to ask what elements of antigen receptor diversification processes limit generalized genomic instability, ie, what safety features prevent the occurrence of oncogenic events in most individuals. Clues to such tumor-suppressor mechanisms may emerge from the study of genes responsible for hereditary lymphoma susceptibility disorders, including ataxia-telangiectasia (AT), Nijmegen breakage syndrome (NBS), and Bloom’s syndrome. In the absence of genetic predisposition, toxic exposures or immune system alterations (eg, such as occurs in acquired immunodeficiency syndrome [AIDS]) may interfere with mechanisms that assure genetic safety in the resolution of DNA breaks. Further understanding of antigen receptor gene diversification in lymphocytes and the regulation of these processes in immunity may therefore yield testable hypotheses about the causes of lymphoma.