Binding sites for the transcriptional regulatory factor nuclear factor kappa B (NF-kappaB) are present in the promoter regions of many of the proinflammatory cytokines and immunoregulatory mediators important in inducing acute inflammatory responses associated with critical illnesses. Because increased activation of NF-kappaB leads to enhanced expression of these proinflammatory mediators, NF-kappaB activation may be a central event in the development of multiple organ dysfunction associated with infection, blood loss, and ischemia-reperfusion injury. NF-kappaB is normally retained in the cytoplasm through its association with the inhibitory molecule I kappaB. Phosphorylation, ubiquination, and proteolysis of I kappaB allows NF-kappaB to translocate to the nucleus and induce transcription, once associated with the transcriptional cofactor CBP. The transcriptional activity of NF-kappaB can be regulated at multiple steps, including the amount of I kappaB present, NF-kappaB subunit composition, and competition for CBP binding. Because of the central role that NF-kappaB occupies in modulating immunoregulatory responses, further understanding of its regulation will be important in designing future therapies able to prevent or minimize acute inflammatory injury associated with critical illness.