In response to different extracellular signals, Rel/NF-κB transcription factors are critical regulators of apoptosis in a variety of cell types. Here we show that in normal B and T cells, expression of the Bcl-2 prosurvival homolog, A1, is rapidly induced in a Rel-dependent manner by mitogens. In B-cell lines derived from c-rel^−/− mice, which like primary cells lacking Rel undergo apoptosis in response to antigen receptor ligation, constitutive expression of an A1transgene inhibits this pathway to cell death. These findings are the first to show that Rel/NF-κB regulates physiologically the expression of a Bcl-2-like protein that is critical for the control of cell survival during lymphocyte activation.