The Rel/NF-kappa B transcription factors represent the paradigm of regulation of transcriptional activation through sub-cellular localization. In unstimulated cells, NK-kappa B exists in an inactive state in the cytoplasm complexed to the inhibitory I kappa B molecules. Upon stimulation, I kappa B is rapidly degraded, freeing NF-kappa B 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 I kappa B molecules, their functions, the mechanisms of I kappa B degradation, and the most common upstream signaling pathway (that is, serine phosphorylation) that leads to I kappa B degradation. Finally, we will discuss alternative mechanisms for induction of NF-kappa B through regulation of I kappa B activity.