There are many circumstances under which a toxin exploits an endogenous receptor or another protein of host origin to work its untoward effects. In most instances, the receptor normally fulfills a function that has nothing to do with the toxin per se; that is, the toxin is not the "natural" ligand. The situation with endotoxin, however, is a remarkable one. The endotoxin receptor evolved to detect endotoxin. Why have mammals maintained a gene that can undermine their survival? The search for the endotoxin receptor answered this question and also revealed the essential function and biological strategy of the Toll-like receptors: principal sensors of the innate immune system.