The bcl-2 gene is a unique proto-oncogene that blocks apoptosis; its product is localized on the inner mitochondrial membrane. In non neoplastic human lymphoid tissues, bcl-2 protein is strongly expressed in the small recirculating lymphocytes of the follicular mantle zone; it is expressed less intensely in T-cell areas, and is almost absent from germinal center cells. Bcl-2 mRNA, in contrast to bcl-2 protein, is strongly expressed on most of the latter cells, a similar phenomenon also being observed in peripheral blood lymphocytes (PBL). Resting PBL express both bcl-2 mRNA and protein, while most lymphoblasts in mitogen-stimulated PBL cultures lose bcl-2 protein and become apoptotic, despite expressing higher levels of mRNA. Posttranscriptional regulation of the bcl-2 gene may cause this paradoxical down-regulation of bcl-2 protein and may play an important role in the clonal selection of lymphocytes. Bcl-2 protein is frequently expressed in follicular lymphomas bearing the t(14;18) chromosomal translocation, but it is also widely expressed in many other B- and T-cell lymphomas without bcl-2 rearrangement, showing that mechanisms other than t(14;18) translocation may deregulate bcl-2 expression. Many lymphoid and myeloid cell lines also express bcl-2 protein with no correlation being shown with differentiation stage. Thus, it is conceivable that bcl-2 protein may play a role in the oncogenesis of many hematolymphoid malignancies by interfering with programmed cell death, in concert with other oncogenes or tumor suppressor genes.