Endotoxin, more accurately referred to as lipopolysaccharide (LPS), is recognized as the most potent microbial mediator implicated in the pathogenesis of sepsis and septic shock. Despite its discovery over one century ago, the fundamental role of endotoxin in most patients with septic shock remains enigmatic and its value as a target for therapeutic intervention continues to be a contentious clinical issue. LPS is viewed by the host as an alarm molecule indicating microbial invasion by gram-negative bacterial pathogens. The release of large quantities of LPS into the bloodstream is clearly deleterious to the host, and this event can precipitate the induction of a potentially lethal array of inflammatory mediators and procoagulant factors. The host response to highly purified LPS can create diffuse endothelial injury, tissue hypo-perfusion, disseminated intravascular coagulation, and refractory shock. Numerous attempts to block endotoxin activity in clinical trials with septic patients have met with inconsistent and largely negative results. The tremendous knowledge gained within the past decade into the precise molecular basis for LPS-mediated cellular activation and tissue injury has generated a new generation of therapies that specifically disrupt LPS signaling. This information should provide the necessary insights to specifically target anti-LPS interventions in the ongoing effort to improve the management of sepsis.