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The Bcl-2 family of proteins are key regulators of apoptosis. Bcl-xL is an anti-apoptotic protein with a high degree of homology to Bcl-2; however, the signals that regulate Bcl-xL and Bcl-2 appear to be different. Levels of Bcl-xL, but not Bcl-2, are increased in response to various survival signals. Furthermore, an inverse correlation between the levels of Bcl-2 and Bcl-xL has been reported for a number of cancers. Although the precise molecules that control Bcl-xL activity are unclear, the STAT, Rel/NF-κB, and Ets transcription factor families have recently been reported to directly regulate the bcl-x gene. Activated Ras, integrin, vitronectin, and hepatocyte growth factor signaling cascades have also been linked to changes in Bcl-xL expression. Bcl-xL can also be affected by post-translational mechanisms. Here we review recent advances in identifying the signaling pathways and factors involved in regulation of the bcl-x gene.