Activation of the cell surface receptor Fas/APO‐1 (CD95) induces apoptosis in lymphocytes and regulates immune responses. The cytoplasmic membrane protein Bcl‐2 inhibits lymphocyte killing by diverse cytotoxic agents, but we found it provided little protection against Fas/APO‐1‐transduced apoptosis in B lymphoid cell lines, thymocytes and activated T cells. In contrast, the cowpox virus protease inhibitor CrmA blocked Fas/APO‐1‐transduced apoptosis, but did not affect cell death induced by gamma‐radiation or serum deprivation. Signalling through Fas/APO‐1 did not down‐regulate Bcl‐2 or induce its antagonists Bax and Bcl‐xS. In Fas/APO‐1‐deficient lpr mice, Bcl‐2 transgenes markedly augmented the survival of antigen‐activated T cells and the abnormal accumulation of lymphocytes (although they did not interfere with deletion of auto‐reactive cells in the thymus). These data raise the possibility that Bcl‐2 and Fas/APO‐1 regulate distinct pathways to lymphocyte apoptosis.