Septic shock is the most severe manifestation of infection and appears to be increasingly common, especially in the intensive care units. Lipopolisaccharides (LPS, endotoxin) are known to be responsible for the initiation of sepsis and septic shock, therefore they can be targets for new preventive and therapeutic strategies. This review focuses on endotoxin-based molecular strategies for the prevention and treatment of Gram-negative sepsis and septic shock.