B lymphocytes contribute to the immune system by the production of antigen-specific antibodies. When naive mature B-lymphocytes recognize antigen with their specific Ig receptors, they will undergo clonal proliferation and differentiation, thereby generating a large number of long-lived memory B cells and plasma cells that produce and secrete antigen-specific antibodies. Recently, we generated new insights on the peripheral B-cell compartment in mice and man, supported by the introduction of a novel molecular assay that quantifies the replication history of B lymphocytes. Our data indicate that naive mature B lymphocytes are able to undergo antigen-independent homeostatic proliferation. Furthermore, the extent of proliferation differs substantially between T-cell dependent and T-cell independent B-cell responses. Thus, three unique proliferation stages occur in the peripheral B-cell compartment. Now that we have identified the B-cell subsets that undergo proliferation, it is a challenge to investigate the initiation and regulation of the proliferation processes. To support the understanding of each of the three proliferation stages, we present our view on the impact of the different proliferation stages on B-cell maturation, the potential molecular mechanisms underlying these processes, and the potential implications in human immunological diseases.