Tumor necrosis factor (TNF)-alpha has been implicated in the induction of hepatocyte apoptosis in a variety of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, and cancer. The binding of TNF to TNF receptor 1 (TNFR1) induces two simultaneous pathways, one leading to cell survival through NF-κB activation and the other cell death via apoptosis. How these pathways are regulated is poorly understood in hepatocytes. Emerging data suggest that there are often aspects of TNFR1-initiate signaling that are unique to hepatocyte. Here we summarize the past and present knowledge of the TNF/TNFR1 system in the liver.