Endotoxin/lipopolysaccharide (LPS) is the major mediator that triggers the cellular and humoral responses of the shock induced by Gram-negative bacteria. The toxic responses of LPS are mediated by various factors and mainly by tumor necrosis factor alpha (TNFalpha). To study the role of TNF and to identify anti-TNF molecules in endotoxic/septic shock, numerous animal models have been utilized. The models described here are among the most widely used and are represented by LPS given at high dose, or at low dose in D-galactosamine-sensitized mice. The endpoints of these models are the survival, the organ toxicity, or the regulation of cytokines, and in particular of TNFalpha. An additional and more complex model of endotoxic/septic shock, the polymicrobial model of cecal ligation and puncture, where a synergistic interaction of several mediators occurs, is then described.