Cytokines are important mediators of the effects observed after the administration of endotoxin. One of them, tumor necrosis factor, is particularly important since it plays a cardinal role in two major endotoxin activities: its antitumor effect and its capacity to induce a systemic inflammatory response syndrome. TNF exerts its activity on a wide variety of target cells by the triggering of two distinct receptor types. TNF-R55 and TNF-R75. They induce distinct intracellular signals but can have cooperative effects. So, their differential triggering or modulation may have clinically relevant consequences. Based upon observations in the mouse, where hTNF does not interact with the TNF-R75 while mTNF triggers both receptor types, we propose that both receptors need to be triggered to obtain lethality after the administration of TNF. Since human TNF has retained antitumor activity, esp. in combination with IFN-gamma, TNF-mutants that are selective agonists for the TNF-R55 might have a broader therapeutic margin. One such human TNF mutant was already shown to be as effective as the wild-type hTNF in a xenograft model. However, several sensitizing agents may mimic TNF-R75 triggering and so make TNF-R55 triggering a lethal challenge. The fact that two such agents, RU38486 and IL-1 have similar effects regarding their kinetics and their capacity to sensitize for the lethality- and IL-6-inducing effect of hTNF may give a hint regarding the mechanism of the sensitizing effect.