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Rheumatoid arthritis (RA) is an immune-mediated disease with synovial inflammation and invasion of the extracellular matrix. While adaptive immunity plays a key role in the pathogenesis of RA, the contribution of innate immune responses has been increasingly appreciated in recent years. Toll-like receptors (TLRs) and cytokines in the rheumatoid synovium can activate signal transduction pathways that induce proinflammatory genes and perpetuate synovitis. Understanding these signaling mechanisms helps us understand the pathogenesis of disease and identify novel therapeutic targets. Among the signaling pathways that are potentially involved in inflammation, the IKK-related kinase, inducible IKK (IKKi or IKKe), appears to play a key role in innate immune responses in the joint and modulates synovial inflammatory responses. This kinase, along with a second IKK-related kinase TANK binding kinase 1 (TBK1), was originally identified as a NF-κB activating enzyme that phosphorylates IkB. It is now clear, however, that this represents only one of several substrates for this family. For instance, IKKi also phosphorylates interferon regulatory factor (IRF) and coordinates the activation of IRF and NF-κB after TLR ligation. IKKi may also link the NF-κB and CCAAT enhancer binding protein (C/EBP) pathways in lipopolysaccharide-stimulated cells. The novel roles for IKKi suggests that it contributes to the signaling pathways involved in synovial inflammation. Moreover, IKKi appears to play a key role in the establishment of an 'antiviral state' through the activation of IRF3 and c-Jun with subsequent production of interferon beta (IFN-β) and other genes involved in host defense. We previously demonstrated that IKKi is constitutively expressed in RA synovial tissue and fibroblast-like synoviocytes (FLS), and that the gene can be induced by cytokine stimulation. More recent studies now show that functional activity of IKKi in cultured synoviocytes is rapidly increased by exposure to proinflammatory cytokines and TLR agonists. We have also shown that IRF3 is activated in RA synovium, which represents an early step in the IKKi-mediated expression of antiviral genes like IFN-β. Additional preliminary data with human FLS suggest that the IKKi pathway can activate other signaling cascades, such as c-Jun, which play a role in assembly of the interferon enhanceosome to increase IFN-β expression. Using FLS from IKKi knockout mice, we have shown that IKKi can act as a key link between TLR/cytokine receptor ligation and expression of cytokines and matrix metalloproteinases. IKKi might serve in an alternative signaling pathway for activation of innate immunity in RA and establishing an anti-viral state in the synovium, especially through the activation of IRF3-driven and c-Jun-driven genes.