Hepatocellular carcinoma (HCC) is the third deadliest and fifth most common human cancer worldwide. Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections along with alcohol and aflatoxin B1 intake are widely recognized etiological agents in HCCs. It is anticipated that HCCs will constitute a major health problem in the next two decades because of the rising incidence of HCV infections in the US. The poor survival rate achieved by current surgical procedures and chemotherapy treatment has prompted the scientific community to gain a better understanding of the molecular events involved in hepatocarcinogenesis in order to define new targets for more effective treatment. Recent findings from several laboratories have implicated constitutive activation of the transcription factor NF-κB as one of the early key events involved in neoplastic progression of the liver. Data is summarized here from recently published studies illustrating a crucial role of NF-κB in bridging the action of growth factors and inflammation to hepatic oncogenesis. Although additional work is needed to fully understand the precise role of NF-κB in the regulation of the various transitions of HCC development, these new findings raise the intriguing possibility that pharmacologic inhibition of NF-κB in the liver could selectively eradicate malignant liver cells without affecting normal liver homeostasis.