Fourteen years after its initial description, the nuclear factor κB (NF-κB) signaling pathway endures as a prime example of rapidly responsive gene regulation (Sen and Baltimore, 1986). Even with the complexities revealed through the elucidation of converging activation pathways and diverging downstream effectors, a generalized scheme of NF-κB signaling remains elegant in its logic:(a) external signals stimulate a kinase (s), such as NF-κB–inducing kinase (NIK), MEKK1, Akt, or TBK1/NAK, which activates the inhibitor of NF-κB protein kinase (IKK);(b) IKK then phosphorylates the inhibitor of NF-κB protein (IκB) on two critical serine residues, which targets IκB for ubiquitination and subsequent degradation by the 26S proteasome;(c) previously held captive in the cytoplasm through its association with IκB, the Rel/NF-κB dimeric transcription factor is now free to enter the nucleus, find its DNA sequence recognition motifs, and regulate transcription (reviewed in Mercurio and Manning, 1999; Ozes et al., 1999; Pomerantz and Baltimore, 1999; Romashkova and Makarov, 1999; Tojima et al., 2000). The ongoing examination of NF-κB signaling has revealed its everexpanding role in stress responses, apoptosis, cell survival, oncogenesis, and development. The list of potent inducers of NF-κB is also diverse and includes proinflammatory stimuli such as tumor necrosis factor α (TNFα), cytokines and interleukin 1ß (IL-1ß), bacterial and viral products, pro-apoptotic and necrotic stimuli ranging from ultraviolet light and-irradiation to oxygen free radicals, and, most recently, cell survival factors, eg, neurotrophins (reviewed by Gerondakis et al., 1998; Foo and Nolan, 1999; Li and Karin, 1999; Middleton et al., 2000). While first discovered as a key regulatory factor of the immune system, NF-κB is now recognized as an important player in the functioning of many organs and cell types. In the past few years, compelling evidence has been accumulating to suggest that the diversity in the outcome of NF-κB activation may be largely a reflection of the cell type and differentiation state of the cell (Ozes et al., 1999; Romashkova and Makarov, 1999; Ernfors, 2000). In the skin, NF-κB plays a particularly central role in epidermal biology. Perpetually subjected to the harmful ultraviolet rays of the sun, the proliferative cells of the epidermis may rely on NF-κB activation for protection and survival (Fisher et al., 1996; Qin et al., 1999; Seitz et al., 2000). More recent gain or loss of function studies in mice suggest an equally important role in balancing growth and differentiation in the epidermis. If correct, this would add yet another provocative function for NF-κB in signaling pathways.