In 1892 Robert Koch's coworker, Richard Pfeiffer, first described bacterial endotoxin as a moiety distinct from secreted, heat-labile exotoxins. Now, some 112 years later, we have extensive knowledge of the mechanism of action of endotoxin, although, amazingly, some pieces of what turned out to be a complex puzzle have only been elucidated in the past few years. Although it had been known since the early 1990s that the cell surface receptor for endotoxin was a protein called CD14, the mechanism by which this receptor signaled the presence of endotoxin remained enigmatic because CD14 lacks a cytoplasmic tail. The solution to this puzzle awaited the discovery of the toll-like receptor 4, a second endotoxin-binding receptor. Yet, many of the sequelae of endotoxin are not via a direct effect on cellular physiology but rather caused by amplified cascades of downstream events that are initiated by endotoxin. Probably the most extensively studied endotoxin-induced cascade is that of the proinflammatory cytokines in which endotoxin initiates tumor necrosis factor α production that, in turn, initiates interleukin (IL) 1β production followed by IL-6 and IL-8. It has been experimentally shown that many of the consequences of endotoxin administration can be reproduced by administration of either tumor necrosis factor α and/or IL-1β.