Endotoxin tolerance refers to the phenomenon that the body or cells show low response or even no response to the restimulation of high-dose lipopolysaccharide after continuous stimulation of low dose of lipopolysac-charide in advance. Endotoxin tolerance is a complex pathophysiological process involving multiple cellular signal pathways，biological molecules and receptor alternations. As yet，the exact mechanism remains unclear. Recent stud-ies have shown that endotoxin tolerance is also associated with certain diseases such as sepsis，diabetes mellitus，cys-tic fibrosis，and cancer. This article reviews in vivo and in vitro models of endotoxin tolerance，toll-like receptor fam-ily and its downstream signal transduction pathways，epigenetics and its regulation of endotoxin tolerance mecha-nism，clinical application and research progress.