The pathophysiology of sepsis and septic shock involves complex cytokine and inflammatory mediator networks. NF-kappaB activation is a central event leading to the activation of these networks. The role of NF-kappaB in septic pathophysiology and the signal transduction pathways leading to NF-kappaB activation during sepsis have been an area of intensive investigation. NF-kappaB is activated by a variety of pathogens known to cause septic shock syndrome. NF-kappaB activity is markedly increased in every organ studied, both in animal models of septic shock and in human subjects with sepsis. Greater levels of NF-kappaB activity are associated with a higher rate of mortality and worse clinical outcome. NF-kappaB mediates the transcription of exceptional large number of genes, the products of which are known to play important roles in septic pathophysiology. Mice deficient in those NF-kappaB-dependent genes are resistant to the development of septic shock and to septic lethality. More importantly, blockade of NF-kappaB pathway corrects septic abnormalities. Inhibition of NF-kappaB activation restores systemic hypotension, ameliorates septic myocardial dysfunction and vascular derangement, inhibits multiple proinflammatory gene expression, diminishes intravascular coagulation, reduces tissue neutrophil influx, and prevents microvascular endothelial leakage. Inhibition of NF-kappaB activation prevents multiple organ injury and improves survival in rodent models of septic shock. Thus NF-kappaB activation plays a central role in the pathophysiology of septic shock.