Sepsis is a syndrome that is initiated by infection and is characterized by a systemic inflammatory response. Genetic polymorphisms affect the susceptibility of individual to this syndrome at the occurrence and development. TLR4 plays an important role in the innate immunity of recognizing pathogenic microorganism. Most studies have been indicated that polymorphism of TLR4 are contributed to the susceptibility of sepsis. In particular, the mutations of Asp299Gly and Thr399Ile of TLR4 are associated with the development and outcome of sepsis. In this review, we summarize the function and signal transduction pathways of TLR4 and the correlation between genetic polymorphism of TLR4 and sepsis.