Lipopolysaccharide, a highly potent endotoxin responsible for severe sepsis, is the major constituent of the outer membrane of gram-negative bacteria. Endothelial cells participate in both innate and adaptive immune responses as the first cell types to detect lipopolysaccharide or other foreign debris in the bloodstream. Endothelial cells are able to recognize the presence of LPS and recruit specific adaptor proteins to the membrane domains of TLR4, thereby initiating an intracellular signaling cascade. However, lipopolysaccharide binding to endothelial cells induces endothelial activation and even damage, manifested by the expression of proinflammatory cytokines and adhesion molecules that lead to sepsis.LPS is involved in both local and systemic inflammation, activating both innate and adaptive immunity. Translocation of lipopolysaccharide into the circulation causes endotoxemia. Endothelial dysfunction, including exaggerated inflammation, coagulopathy and vascular leakage, may play a central role in the dysregulated host response and pathogenesis of sepsis. By discussing the many strategies used to treat sepsis, this review attempts to provide an overview of how lipopolysaccharide induces the ever more complex syndrome of sepsis and the potential for the development of novel sepsis therapeutics.To reduce patient morbidity and mortality, preservation of endothelial function would be central to the management of sepsis.© 2023. BioMed Central Ltd., part of Springer Nature.