Cellular stressors such as UV irradiation, chemical irritants, or an immune system challenge in an otherwise healthy host induce the production and release of cytokines, such as tumor necrosis factor (TNF) alpha, which are powerful regulators of tissue homeostasis. TNFalpha, an important mediator of inflammation in the skin and mucosa, often represents the first physiological response to such noxious stimuli. TNFalpha not only acts systemically to promote inflammation, but also locally at the site of the stimulus to modulate cell growth and survival. It has been demonstrated previously that epithelial cells undergo growth arrest and differentiation in the presence of TNFalpha. However, the mechanism of this response is not well understood. Here we show that in primary cultures of human foreskin keratinocytes, TNFalpha mediates cellular growth arrest through activation of the transcription factor NF-kappaB. The cdk inhibitor p21(Cip1/Waf1) is activated through NF-kappaB and is an important mediator of this growth arrest response. In addition, TNFalpha-treated cell populations are markedly less susceptible to apoptosis by UV irradiation and this cytoprotective effect is at least in part mediated by p21(Cip1/Waf1) as well.