The number of lymphocytes in an animal is remarkably constant despite antigen-driven proliferation and a high rate of B-cell lymphopoiesis. This reflects the relatively brief lifespan of many newly generated B cells and argues for a well-regulated death mechanism. Even so, a secondary immune response can be generated years after a primary exposure to antigen. Antigen that might restimulate B cells persists for extended periods on follicular dendritic cells in the light zone of germinal centres. Antigen-binding B cells have also been found months after the end of obvious cell division. The precise signal that enables certain B cells to emerge as long-term surviving memory cells is unknown. Bcl-2, an inner mitochondrial membrane protein, blocks programmed cell death in B cells. We report here that this proto-oncogene maintains immune responsiveness. Transgenic mice overproducing Bcl-2 have a long-term persistence of immunoglobulin-secreting cells and an extended lifetime for memory B cells.