Hepatocyte cell death is a universal feature of inflammatory liver diseases. The observation that mice deficient in the activation of nuclear factor-κB (NF-κB) are not viable because of excessive hepatocyte apoptosis induced by tumor necrosis factor (TNF) made it crystal-clear that NF-κB plays a central role in protecting hepatocytes against TNF-induced cell death. Also during TNF-mediated liver injury, NF-κB was shown to have an essential anti-apoptotic effect, underscoring the therapeutic importance of understanding its underlying molecular mechanisms. For a long time, the ability of NF-κB to induce the expression of a variety of anti-apoptotic proteins was thought to be solely responsible for its cytoprotective effects. However, during the past few years it has become clear that NF-κB-mediated inhibition of cell death also involves attenuating TNF-induced activation of c-Jun activating kinase (JNK). Whereas transient activation of JNK upon TNF treatment is associated with cellular survival, prolonged JNK activation contributes to cell death. Several studies have shown that NF-κB activation inhibits the sustained phase of TNF-induced JNK activation and thus protects cells against TNF cytotoxicity. In this review, we will discuss the various mechanisms by which NF-κB activation blunts TNF-induced JNK activation, including the induction of JNK inhibitory proteins and controlling the levels of reactive oxygen species (ROS). Moreover, because the cytoprotective effects of NF-κB activation are particularly important in liver physiology, we will put each of these JNK-inhibitory mechanisms into a ‘hepatic perspective’ by discussing their role in various mouse models of TNF-mediated liver injury.