The liver plays a central role in the transformation anddegradation of endogenous and exogenous chemicals,and in the removal of unwanted cells such as damaged,genetically mutated and virus-infected cells. Because ofthis function, the liver is susceptible to toxicity causedby the products generated during these natural occur-rences. Hepatocyte death is the major feature of liverinjury. In response to liver injury, specific intracellularprocesses are initiated to maintain liver integrity. Inflam-matory cytokines including tumor necrosis factor (TNF)aand interleukin-6 (IL-6) are key mediators of these pro-cesses and activate different cellular response such asproliferation, survival and death. TNFainduces specificsignaling pathways in hepatocytes that lead to activationof either pro-survival mediators or effectors of cell death.Whereas activation of transcription factor NF-kBpro-motes survival, c-Jun N-terminal kinases (JNKs) andcaspases are strategic effectors of cell death in theTNFa-mediated signaling pathway. This review summa-rizes recent advances in the mechanisms of TNFa-induced hepatotoxicity and suggests that NF-kB plays aprotective role against JNK-induced hepatocyte death.Identification of the mechanisms regulating interplaybetween the NF-kB and JNK pathways is required in thesearch for novel targets for the treatment of liver disease,including hepatitis and hepatocellular carcinoma.