Transcription factors of the nuclear factor ?B (NF-?B)/Rel family play a pivotal role in inflammatory and immune responses. There are five family members in mammals: RelA, c-Rel, RelB, NF-?B1 (p105/p50), and NF-?B2 (p100/p52). Both p105 and p100 are proteolytically processed by the proteasome to produce p50 and p52, respectively. Rel proteins bind p50 and p52 to form dimeric complexes that bind DNA and regulate transcription. In unstimulated cells, NF-?B is sequestered in the cytoplasm by I?B inhibitory proteins. NF-?B-activating agents can induce the phosphorylation of I?B proteins, targeting them for rapid degradation through the ubiquitin-proteasome pathway and releasing NF-?B to enter the nucleus where it regulates gene expression. NIK and IKK? (IKK1) regulate the phosphorylation and processing of NF-?B2 (p100) to produce p52, which translocates to the nucleus. Following IKK-mediated phosphorylation of p105 NF-?B at multiple sites (Ser921, 923, 927, and 932) on its carboxy-terminus, SCF/?-TrCP mediated processing produces the 50 kDa active form p50.