Intoxication with different natural toxins or man-made toxicants has been associated with the induction of tumor necrosis factor alpha (TNF). These include endotoxin, superantigens, Pseudomonas aeruginosa exotoxin A, bacterial DNA, T cell stimulatory agents such as agonistic anti-CD3 mAbs or concanavalin A, alpha-amanitin, paracetamol, ethanol, carbon tetrachloride, dioxin, and dimethylnitrosamine. In this paper we compile and discuss the current knowledge on the pathophysiological role of TNF during intoxication with all mentioned toxins and toxicants. A possible role of gut-derived endotoxin in several TNF-dependent toxic events has been considered. The development of pharmaceuticals that selectively interfere with the detrimental pathways induced by TNF during intoxication with bacteria, viruses, drugs, or other chemicals requires detailed knowledge of the signaling pathways originating from the two TNF receptors (TNFR1 and TNFR2). Major characteristics of these signaling pathways are described and put together.