Endotoxin is a unique molecule because it represents an important probe for investigating the humoral and cellular basis of septic shock. Endotoxin administration to humans provides an opportunity to evaluate the earliest responses that are activated after exposure to an important bacterial component. Many alterations in organ function and circulating mediators can be evaluated in this model. These changes are qualitatively similar to changes that occur during sepsis and septic shock. The applications of new technologies to this model are useful adjuncts to define mechanisms of acute inflammatory responses. Defining these pathways and their interactions may allow a better understanding of the factors that can be controlled or altered during critical illness.