Bcl-2-family proteins are key regulators of the apoptotic response. Here, we demonstrate that the pro-survival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-κB. We show that bfl-1 gene expression is dependent on NF-κB activity and that it can substitute for NF-κB to suppress TNFα-induced apoptosis. bfl-1 promoter analysis identified an NF-κB site responsible for its Rel/NF-κB-dependent induction. The expression of bfl-1 in immune tissues supports the protective role of NF-κB in the immune system. The activation of Bfl-1 may be the means by which NF-κB functions in oncogenesis and promotes cell resistance to anti-cancer therapy.