The transcription factor, nuclear factor-kappa B (NF-kappa B), is a dominant regulator of the expression of hundreds of genes, many of which play important roles in the regulation of inflammation and programmed cell death (apoptosis). Since the discovery of NF-kappa B in the mid 1980s, this transcription factor has been the subject of intense investigation. Excess or inappropriate activation of NF-kappa B has been observed in human inflammatory bowel disease and in a host of other inflammatory diseases and type of cancer. Functional studies in animals have shed light on the role of NF-kappa B in broader pathophysiological contexts. From such studies, it has become quite clear that NF-kappa B plays unique and distinct functions in different cell types. Because of the importance of NF-kappa B in signaling inflammation, and in inhibiting programmed cell death, many pharmaceutical companies are developing small-molecule inhibitors of this pathway. In this article, we evaluate the relative pros and cons of blocking NF-kappa B as a therapeutic approach for inflammatory bowel disease. On the basis of the results of studies in animals that have primarily used genetic approaches to inhibit NF-kappa B activity, we suggest that there are certain niche indications for blocking NF-kappa B in inflammatory bowel disease that offer particular promise.