Tumor Necrosis Factor α (TNFα) is a pro-inflammatory cytokine that plays important roles in different biological processes, including the induction of other cytokines. One of the most important downstream signaling targets activated by TNFα is the NF-κB transcription factor, which has been identified to be involved in inflammatory, anti-apoptotic, and immune responses. Stimulation of cells with TNFα triggers activation of NF-κB through various signaling molecules, including TRAF2, RIP, MAP3K, and the IKK complex. Recently, numerous studies have been performed to explore the detailed mechanism by which NF-κB is activated upon TNFα stimulation. Current understanding of this pathway has been focused on the identification of signaling components, the role of post-translational modification and the sub-cellular translocation of those components. Additionally, more negative regulators in the TNF–IKK pathway are emerging.