Neutralization of endotoxin (lipopolysaccharide) would be of considerable benefit in the treatment of Gram-negative sepsis. Administration of anti-lipopolysaccharide antibodies is an old approach that has been renewed by improvements in monoclonal antibody technology. Experimental and clinical studies of antibodies directed at the conserved core region of lipopolysaccharide or at the lipid A are discussed. Some of these antibodies appear to be protective in animal models or in clinical trials, but discrepant results have been reported and the mechanism of the postulated protection was not clarified. Despite the availability of a monoclonal anti-lipid A antibody on the market in some European countries, this type of treatment should still be considered of unclear value until further experimental and clinical studies have reinvestigated the protection afforded by these antibodies. The use of detoxified lipid A analogs with lipopolysaccharide antagonist properties is another promising strategy that is discussed briefly in this review. Recently, substantial progress has been made in understanding how lipopolysaccharide triggers the immune system. A family of proteins possessing lipopolysaccharide-binding sites has been discovered. These proteins have a striking homology in DNA sequence, but they have different functions. The biological role of these proteins is now being actively investigated. New strategies to improve the outcome of Gram-negative sepsis may result from this research.