Transcription factor NF-κB regulates the physiological response to a variety of stimuli. The NF-κB pathway has served as a paradigm for analyzing the impact of the covalent protein modifier ubiquitin on signal transduction. The discovery in the early 1990s that degradation of cytosolic NF-κB inhibitors (IκBs) is mediated by the ubiquitin proteasome system (UPS) was the first example for a direct involvement of ubiquitination in cellular signaling. By now it has become clear that the role of the ubiquitin system in the NF-κB pathway extends far beyond triggering IκB destruction. The IκB kinase (IKK) complex is the key regulator of NF-κB. Attachment of ubiquitin chains to the IKK complex and to further upstream components drives NF-κB signaling pathways by promoting the clustering of the signaling network. Whereas ubiquitin conjugation serves a positive function in the NF-κB pathway, ubiquitin deconjugation acts as a negative regulatory feedback mechanism that is critically involved in balancing the strength and the duration of the NF-κB response. Moreover, inactivation of deconjugating enzymes can cause sustained NF-κB activity under pathological conditions like chronic inflammation or cancer. Here we review the impact of the ubiquitin system on the NF-κB signaling network by putting a focus on the enzymes that help to shape the plasticity of the NF-κB response.