The transcription factors of the Rel/NF-κB family are key regulators of immune and inflammatory responses and contribute to lymphocyte proliferation, survival, and oncogenesis. The absolute correlation between the antiapoptotic and oncogenic activities of the Rel/NF-κB oncoprotein v-Rel emphasizes the importance of characterizing the death antagonists under NF-κB control. Our recent finding that the prosurvival Bcl-2 homolog Bfl-1 (also called A1) is a direct transcriptional target of NF-κB raised the issue of whether NF-κB is a specific or global regulator of death antagonists in the Bcl-2 family. Here, we demonstrate that NF-κB differentially regulates the expression of particular Bcl-2-related death inhibitors and that it directly activates the expression of Bcl-x_L. While Bcl-x_L was significantly upregulated by c-Rel and RelA, Bcl-2 was not. Importantly, stimuli that activate endogenous NF-κB factors also upregulated bcl-x gene expression and this effect was antagonized by an inhibitor of NF-κB activity. The expression of bcl-x suppressed apoptosis in the presence or absence of NF-κB activity. Functional analysis of the bcl-x promoter demonstrated that it is directly controlled by c-Rel. These results establish that NF-κB directly regulates the expression of distinct prosurvival factors in the Bcl-2 family, such as Bcl-x_L and Bfl-1/A1. These findings raise the possibility that some of these factors may contribute to oncogenesis associated with aberrant Rel/NF-κB activity.