Sepsis is a clinical syndrome defined as a systemic inflammatory response to infection. Eritoran is a synthetic lipid A derivative that competes with lipopolysaccharide in binding to the identical site of myeloid differentiation-2/toll-like receptor 4 complex. Eritoran is effective in decreasing the septic mortality of Gram-negative bacteria-infected animals. Eritoran has been highlighted as a candidate drug for treatment of endotoxemia in phase I clinical studies with healthy human volunteers. A phase II trial of eritoran has been conducted in patients with severe sepsis. Intravenous infusion of eritoran reduced the mortality rate, as compared with the placebo group, in sepsis patients at a high risk of mortality according to acute physiology and chronic health evaluation-II scores. A phase III study of eritoran was completed in 2011. The results appear to be disappointing as no statistically significant difference in all-cause mortality was observed between the eritoran treatment group and the placebo group on day 28 in sepsis patients with a high risk of death. In this review, we focus on the rationale for the use of eritoran in treatment of sepsis as well as its clinical applications.