The transcription factor NF-κB plays an important role in the induction of proinflammatory factors. NF-κB is sequestered in the cytoplasm by its inhibitory protein, IκB. Agents that stimulate NF-κB activation induce the phosphorylation of IκB by two IκB kinase (IKK) subunits, IKKα and IKKβ. The phosphorylation targets it for rapid degradation through ubiquitin-proteasome pathway, thereby releasing NF-κB to enter the nucleus. Several mitogen-activated protein kinase kinase kinases (MAP3Ks) play critical roles in NF-κB activation mediated through IKK pathway. We have found that TGFβ activated kinase 1 (TAK1), a member of the MAP3K family, stimulates NF-κB activation. TAK1 interacts with and activates IKKα and IKKβ. Furthermore, TNFα, but not TGFβ, activates TAK1 and the kinase negative TAK1 acts as a dominant negative inhibitor against TNFα-induced NF-κB activation. These results demonstrated a novel signaling pathway to NF-κB activation through TAK1, in which TAK1 may act as a regulatory kinase of IKKs.