The NF-κB family of transcription factors is activated by various stimuli, with members of the TNF cytokine family being among the best-characterized inducers. Research on NF-κB and TNF has been closely intertwined for over 25 years, with knock-out mice unable to activate NF-κB showing embryonic lethality, but deletion of TNF or TNFR1 rescuing these mice. This review explores the general mechanisms of TNF cytokine signaling, focusing on the upstream signaling events leading to the activation of canonical and noncanonical NF-κB pathways by TNFR1 and CD40, respectively. The canonical pathway involves the inducible degradation of IκBα through phosphorylation by IKKα, while the noncanonical pathway involves the inducible processing of p100 to p52 through the activation of IKKα by NIK. Adapter proteins such as TRADD, TRAF2, and RIP1 play crucial roles in recruiting IKK and other signaling molecules to the receptor complex. The termination of NF-κB signaling involves mechanisms such as receptor downregulation, induction of IκB transcription, and degradation of active NF-κB dimers. The noncanonical pathway is particularly important in B cell biology and is regulated by NIK, which stabilizes and activates IKKα.The NF-κB family of transcription factors is activated by various stimuli, with members of the TNF cytokine family being among the best-characterized inducers. Research on NF-κB and TNF has been closely intertwined for over 25 years, with knock-out mice unable to activate NF-κB showing embryonic lethality, but deletion of TNF or TNFR1 rescuing these mice. This review explores the general mechanisms of TNF cytokine signaling, focusing on the upstream signaling events leading to the activation of canonical and noncanonical NF-κB pathways by TNFR1 and CD40, respectively. The canonical pathway involves the inducible degradation of IκBα through phosphorylation by IKKα, while the noncanonical pathway involves the inducible processing of p100 to p52 through the activation of IKKα by NIK. Adapter proteins such as TRADD, TRAF2, and RIP1 play crucial roles in recruiting IKK and other signaling molecules to the receptor complex. The termination of NF-κB signaling involves mechanisms such as receptor downregulation, induction of IκB transcription, and degradation of active NF-κB dimers. The noncanonical pathway is particularly important in B cell biology and is regulated by NIK, which stabilizes and activates IKKα.