Rel/NF-kB transcription factors include a collection of proteins, conserved from Drosophila to humans (Figure 1). Among model organisms, these transcription factors are notably absent in yeast and C. elegans; in part, this may be because one of the primary roles of these factors is to control a variety of physiological aspects of immune and inflammatory responses. A pathway similar to the Rel/NF-kB signaling pathway may also control certain defense responses in plants. The Rel/NF-kB proteins are related through a highly conserved DNA-binding/dimerization domain called the Rel homology (RH) domain. However, they can be divided into two classes based on sequences C-terminal to the RH domain. Members of one class (p105, p100, and Drosophila Relish) have long C-terminal domains that contain multiple copies of ankyrin repeats, which act to inhibit these molecules. Members of this class become active, shorter DNA-binding proteins (p105 to p50, p100 to p52) by either limited proteolysis or arrested translation. As such, members of this first class are generally not activators of transcription, except when they form dimers with members of the second class of Rel/NF-kB transcription factors. The second class includes c-Rel (and its homologue v-Rel), RelB, RelA (p65), Dorsal, and Dif. These Rel proteins contain C-terminal activation domains, which are often not conserved at the sequence level across species, even though they can activate transcription in a variety of species. Rel/NF-kB transcription factors bind to 10 base pair DNA sites (kB sites) as dimers. All vertebrate Rel proteins can form homodimers or heterodimers, except for RelB, which can only form heterodimers. This combinatorial diversity contributes to the regulation of distinct, but overlapping, sets of genes, in that the individual dimers have distinct DNA-binding site specificities for a collection of related kB sites. NF-kB commonly refers to a p50-RelA heterodimer, which is one of the most avidly forming dimers and is the major Rel complex in most cells. The activity of NF-kB is tightly regulated by interaction with inhibitory IkB proteins. As with the Rel/NF-kB proteins, there are several IkB proteins (see Karin, 1999), which have different affinities for individual Rel/NF-kB complexes, are regulated slightly differently, and are expressed in a tissuespecific manner. The best-studied Rel-IkB interaction is that of IkBa with NF-kB, and this interaction blocks the ability of NF-kB to enter the nucleus and bind to DNA. From biochemical studies and, more recently, direct structural determinations (Chen and Ghosh, 1999), it is clear that IkBa makes multiple contacts with NF-kB. These interactions cover the nuclear localization sequence of NF-kB and interfere with sequences important for DNA binding. Thus, in most cells, NF-kB is present as a latent, inactive, IkB-bound complex in the cytoplasm. When a cell receives any of a multitude of extracellular signals (see Pahl, 1999), NF-kB rapidly enters the nucleus and activates gene expression. Thus, a key step for controlling NF-kB activity is the regulation of the IkB-NF-kB interaction. Many of the molecular details of this control are now understood (see Karin, 1999; Figure 2). Almost all signals that lead to activation of NF-kB converge on a high molecular weight complex that contains a serine-specific IkB kinase (IKK). The IKK is an unusual kinase in that it contains two related kinases, IKKa and IKKb, that are active as a dimer. Activation of IKK leads to the phosphorylation of two specific serines near the N terminus of IkBa, which targets IkBa for ubiquitination and degradation by the proteasome. The unmasked NF-kB can then enter the nucleus to activate target gene …