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Nuclear factor-kappa B (NF-κB) is a key transcriptional regulator of innate and adaptive immunity. This review highlights new insights into the functions of NF-κB in normal homeostasis and specific disease processes in the intestinal tract.Inflammatory bowel disease and experimental intestinal inflammation are characterized by NF-κB activation and increased expression of proinflammatory NF-κB target genes. Accordingly, NF-κB inhibition protects against chronic intestinal inflammation and necrotizing enterocolitis in animal models. However, recent findings suggest that NF-κB has not only proinflammatory but also tissue-protective functions. Thus, genetic ablation of the regulatory subunit, IκB kinase (IKK)γ, of the central kinase complex required for NF-κB activation, IKK, or of both kinase subunits, IKKα and IKKβ, in intestinal epithelial cells causes spontaneous murine colitis. Pharmacological inhibition of IKKβ, and loss of IKKβ or NF-κB p65 in the epithelium, sensitizes mice to acute inflammatory and injurious challenges. Deficiency in Toll-like receptor 5, a strong activator of NF-κB, results in spontaneous colitis and exacerbates mucosal inflammatory responses to Salmonella infection. Conversely, Toll-like receptor 5 stimulation confers radioprotection in the intestine.NF-κB has multiple, often opposing functions in the intestine. Antiapoptotic actions of NF-κB in intestinal epithelial cells dominate tissue responses to many acute inflammatory and injurious challenges, whereas proinflammatory and cell survival functions of NF-κB in macrophages and T cells govern chronic intestinal inflammation.