Natural antibodies arise independently of known antigenic stimulation, are mostly IGM, polyreactive, and are generally encoded by V genes in germline configuration. Polyreactive IgM natural antibodies are produced by mainly B-1 cells which account for most of the B cell repertoire in the fetus and neonate, and possibly play a major role in the development and physiology of the human B cell repertoire. Although endowed with self-reactivity, natural antibodies also bind exogenous antigens [73, 74]. Exposure to environmental antigens is not necessary for the emergence of natural antibody-producing cell precursor clones to exogenous antigens, as suggested by the significant population of B cells capable of producing antibodies to a variety of bacterial antigens in germ-free animals. Because of their ability to bind a variety of exogenous antigens, including those on bacteria and viruses, natural antibodies play a major role in the primary line of defense against infections. A central issue related to the understanding of the physiopathologic roles of natural antibodies is whether precursors of cells producing natural antibodies, B-1a and B-1b lymphocytes, are capable of undergoing an antigen-driven clonal selection process, thereby producing autoantibodies with a high affinity for the selecting antigen. In this respect, we have clearly established that B-1 cells can express a hypermutation mechanism similar to that of conventional (B-2) cells. Furthermore, we have shown by gene shuffling, site-directed mutagenesis, and in vitro human Ig gene expression, that the main structural correlate for antibody polyreactivity is provided by the somatically generated H chain CDR3. We have also shown that this Ig V region provides the main structural correlate for antigen-binding in monoreactive antigen-induced autoantibodies. These findings in the human are at the basis of our proposed structure-function model in which the antigen binding features of the germline template antibody are dictated by the somatically generated H chain CDR3, and perhaps, but at a lower degree, L chain CDR3; the point-mutation changes underlying the antigen-driven affinity maturation process would impact mainly the Ig V gene encoded segments. This structure-function model is being tested in our laboratory by analyzing the antigen binding activity of somatically mutated polyreactive autoantibodies that have been structurally reverted to their original putative unmutated configuration. Precise identification of the Ig gene and/or somatic recombination products mediating recruitment of unmutated B cell clonotypes, as well as those that are preferentially modified by an antigen-dependent selection process, should further our understanding of the mechanisms that shape the B cell repertoire in development and disease.