gp130-linked cytokines such as interleukin-6 (IL-6) stimulate the formation of tyrosine-phosphorylated signal transducer and activator of transcription 3 (P-STAT3), which activates many genes, including the STAT3 gene itself. The resulting increase in the concentration of unphosphorylated STAT3 (U-STAT3) drives a second wave of expression of genes such asRANTES,IL6,IL8,MET, andMRASthat do not respond directly to P-STAT3. Thus, U-STAT3 sustains cytokine-dependent signaling at late times through a mechanism completely distinct from that used by P-STAT3. Many U-STAT3-responsive genes have κB elements that are activated by a novel transcription factor complex formed when U-STAT3 binds to unphosphorylated NFκB (U-NFκB), in competition with IκB. The U-STAT3/U-NFκB complex accumulates in the nucleus with help from the nuclear localization signal of STAT3, activating a subset of κB-dependent genes. Additional genes respond to U-STAT3 through an NFκB-independent mechanism. The role of signal-dependent increases in U-STAT3 expression in regulating gene expression is likely to be important in physiological responses to gp130-linked cytokines and growth factors that activate STAT3, and in cancers that have constitutively active P-STAT3.