V(D)J recombination not only comprises the molecular mechanism that insures diversity of the immune system but also constitutes a critical checkpoint in the developmental program of B and T lymphocytes. The analysis of human patients with severe combined immune deficiency (SCID) has enabled (and will enable in the future) the discovery of important factors involved in this reaction. The finding that the V(D)J recombinase apparatus includes components of the general DNA repair machinery of the cells has provided some new and interesting insights into the role of V(D)J recombination deficiency in the development of lymphoid malignancies, a hypothesis that has been tackled and proven in several animal models.