Endotoxin is a lipopolysaccharide contained within the cell wall of Gram-negative bacteria. This molecule initiates a host inflammatory response to Gram-negative bacterial infection. An adequate inflammatory response likely enhances host survival by mediating clearance of infection and bacterial toxins. Unfortunately, this same host response can also produce dysfunction of multiple organ systems and mortality. This article focuses on the history of our understanding of the role of endotoxin in human septic shock. These pathophysiologic connections have led to therapies directed at endotoxin. Unfortunately, antiendotoxin therapy has not achieved significantly improved outcome in humans with severe sepsis. This may represent lack of antiendotoxin efficacy in the compounds used, or a failure of the investigative approach. Interest in antiendotoxin therapies persists, while investigators express more humility in their understanding of endotoxin's role in the pathophysiology of septic shock.