OBJECTIVE: To analyze the implications for therapeutic advances in the treatment of sepsis and septic shock based on the mechanisms underlying the response to microbial infection. DATA SOURCES: Clinical trials and experimental models designed to determine the key mechanisms involved in cellular and molecular processes of inflammatory reactions. STUDY SELECTION: Analyses of normal immune reactions to microbial infection, processes involved in the development of sepsis, and reasons for frequent failure of regimens based on current therapeutic rationales. DATA EXTRACTION/SYNTHESIS: Review of the data suggests that the dysregulation of the immune system resulting in sepsis/septic shock is ineffectually blocked by interfering with the action of inflammatory mediators or cascades, as these processes may be too complex to be easily antagonized. Rather, blockade of the action of microbial products or of the intracellular processes activated by receptor interaction with these products may provide a more promising therapeutic alternative. CONCLUSIONS: The sepsis syndrome induced by microbial pathogens reflects excessive stimulation of the processes of innate immunity. Bacterial components reacting with specific receptors activate intracellular processes, resulting in the release of excessive amounts of mediators of inflammation as well as triggering multiple complex proteolytic cascades. Blockade or antagonism of the actions of individual intermediary messenger molecules has proved therapeutically unsuccessful, because blockade of mediators alone does not block the direct activation of processes such as coagulation and complement. The dysregulation that characterizes sepsis may be amenable to blockade of the bacterial components or to the intracellular pathways triggered by these products.