Deregulation of the apoptotic program is considered an important cause in liver disease. It became clear that the cytokine tumour necrosis factor (TNF) is of specific interest in this context. Therefore, from a clinical point of view, therapeutic control of TNF-receptor signalling pathways is highly desirable. These TNF-initiated signalling pathways result in a direct apoptotic response as well as potent activation of proinflammatory gene expression via activation of the transcription factor nuclear factor-kappa B (NF-kappaB). Since the latter pathway contributes to a series of liver pathologies, inhibition of hepatic NF-kappaB activation was viewed as a potential therapy for liver injury. However, the more recent finding that NF-kappaB activation in hepatocytes is anti-apoptotic shows that NF-kappaB signalling represents a problematic therapeutic target. Here we review the role of TNF and NF-kappaB in liver pathophysiology, and the underlying mechanisms of hepatocyte sensitisation to TNF toxicity in vivo. Based on this knowledge, we suggest some potential strategies for the treatment of TNF-mediated liver disease.