SummaryDespite the use of increasingly potent antibiotics and aggressive cardiovascular monitoring and support, Gram-negative bacteremia and ensuing sepsis and septic shock remain a leading cause of morbidity and mortality after surgery and in critically ill patients.In previous years several new agents and techniques have been developed to improve management and outcome of severe Gram-negative infections. A recently introduced treatment is passive immunotherapy by administration of poly-or monoclonal antiendotoxin antibodies.The current view-sustained by experimental and human studies-on the mechanism of protection afforded by immunotherapy is that the harmful effects of endotoxin are neutralized by cross-reactive antibodies to the core glycolipid structure of rough mutant Gram-negative bacilli.Two recent large clinical trials reported impressive results achieved through the use of monoclonal antiendotoxin antibodies in certain subgroups of patients with Gram-negative sepsis. However, this treatment is empirical, expensive and it does not affect overall sepsis mortality.Cytokines such as tumor necrosis factor alpha and interleukin-1 play api votal role in sepsis. Experimental studies suggest that specific antagonism of the mediators might offer great perspectives for the treatment of Gram-negativesepsis.An early multi-pharmacological approach aimed a interruption of multiple steps underlying the inflaflamatory septic cascade will probably constitute the most promising future treatment of severe Gramnegative infectious disease.