This review discusses the current understanding of mechanisms that mediate activation of the transcription factor nuclear factor-kappaB (NF-kappaB) and how such activation could in turn mediate reperfusion injury. NF-kappaB regulates the expression of several genes involved in inflammation, the immune response, apoptosis, cell survival and proliferation. Many of these same genes are activated during reperfusion injury. The rationale for considering inhibiting NF-kappaB activation as a promising molecular target for ameliorating reperfusion injury in the brain during stroke, the heart during myocardial infarction and the intestines following prolonged ischemia is discussed on the basis of a new understanding of the mechanisms by which NF-kappaB is activated. A complete anthology of the reperfusion injury literature is beyond the scope of this article and the authors apologize to any investigator not cited for their contributions.