Nuclear factor-κB (NF-κB) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-κB in the diseased liver. In vivo studies using rodent models of liver disease and cell-targeted perturbation of NF-κB activity have revealed complex and multicellular functions in hepatic inflammation, fibrosis, and the development of hepatocellular carcinoma—a process we have termed the “inflammation-fibrosis-cancer axis”. This review summarizes the current state of knowledge and provides insight into the vast complexity of the hepatic NF-κB signaling system, which should provide a rich source of new therapeutic targets. (HEPATOLOGY 2007;46:590–597.)