The Rel/NF-κB transcription factors represent the paradigm of regulation of transcriptional activation through subcellular localization. In unstimulated cells, NF-κB exists in an inactive state in the cytoplasm complexed to the inhibitory IκB molecules. Upon stimulation, IκB is rapidly degraded, freeing NF-κB to translocate to the nucleus and to activate the expression of its target genes. In this chapter, we will summarize what is known about the structure of IκB molecules, their functions, the mechanisms of IκB degradation, and the most common upstream signaling pathway (that is, serine phosphorylation) that leads to IκB degradation. Finally, we will discuss alternative mechanisms for induction of NF-κB through regulation of IκB activity.