Activation of the noncanonical NF-kappaB signaling pathway involved in the proteolytic processing of NF-kappaB p100 to p52 is tightly regulated, and overproduction of p52 leads to lymphocyte hyperplasia and transformation. We have demonstrated that active but not latent Stat3, expressed in many types of human cancers involved in cell proliferation and survival, induces p100 processing to p52 by activation of IKKalpha and subsequent phosphorylation of p100. The Stat3-mediated p100 processing to p52 requires activation of Stat3 by the acetyltransferase activity of cAMP-response element-binding protein (CREB)-binding protein (CBP)/p300. A mutant of Stat3 defective in acetylation blocked Stat3-mediated p100 processing to p52 and acted as a dominant negative in blocking the production of p52. Furthermore, overexpression of p52 protected cells from apoptotic cell death. Thus, activation of the processing of p100 to p52 by Stat3 may represent one of the common pathways used by cancer cells to survive and escape therapy.