Specialized forms of physiologic cell death lacking certain characteristic morphologic features of apoptosis occur in terminally differentiating tissues, such as in the outer cell layers of epidermis. In these cell layers, NF-κB translocates from the cytoplasm to the nucleus and induces target gene expression. In light of its potent role in regulating apoptotic cell death in other tissues, NF-κB activation in these cells suggests that this transcription factor regulates cell death during terminal differentiation. Here, we show that NF-κB protects normal epithelial cells from apoptosis induced by both TNFα and Fas, whereas NF-κB blockade enhances susceptibility to death via both pathways. Expression of IκBαM under control of keratin promoter in transgenic mice caused a blockade of NF-κB function in the epidermis and provoked premature spontaneous cell death with apoptotic features. In normal tissue, expression of the known NF-κB–regulated antiapoptotic factors, TRAF1, TRAF2, c-IAP1, and c-IAP2, is most pronounced in outer epidermis. In transgenic mice, NF-κB blockade suppressed this expression, whereas NF-κB activation augmented it, consistent with regulation of cell death by these NF-κB effector proteins. These data identify a new role for NF-κB in preventing premature apoptosis in cells committed to undergoing physiologic cell death and indicate that, in stratified epithelium, such cell death normally proceeds via a distinct pathway that is resistant to NF-κB and its antiapoptotic target effector genes.J. Clin. Invest.105:253–260 (2000).