The nuclear factor‐κB (NF‐κB) signaling pathway is a busy ground for the action of the ubiquitin–proteasome system; many of the signaling steps are coordinated by protein ubiquitination. The end point of this pathway is to induce transcription, and to this end, there is a need to overcome a major obstacle, a set of inhibitors (IκBs) that bind NF‐κB and prohibit either the nuclear entry or the DNA binding of the transcription factor. Two major signaling steps are required for the elimination of the inhibitors: activation of the IκB kinase (IKK) and degradation of the phosphorylated inhibitors. IKK activation and IκB degradation involve different ubiquitination modes; the latter is mediated by a specific E3 ubiquitin ligase SCF^β‐TrCP. The F‐box component of this E3, β‐TrCP, recognizes the IκB degron formed following phosphorylation by IKK and thus couples IκB phosphorylation to ubiquitination. SCF^β‐TrCP‐mediated IκB ubiquitination and degradation is a very efficient process, often resulting in complete degradation of the key inhibitor IκBα within a few minutes of cell stimulation. In vivo ablation of β‐TrCP results in accumulation of all the IκBs and complete NF‐κB inhibition. As many details of IκB‐β‐TrCP interaction have been worked out, the development of β‐TrCP inhibitors might be a feasible therapeutic approach for NF‐κB‐associated human disease. However, we may still need to advance our understanding of the mechanism of IκB degradation as well as of the diverse functions of β‐TrCP in vivo.