Background S100A9 and its binding partner S100A8 are important members of S100 calcium-binding protein family, which have extensive functions and participate in multiple biological processes. Objective This review aims to provide an update of S100A9 in sepsis, and also to discuss its role in immune regulation, as well as the mechanisms. Content This review includes the following aspects about S100A9: characteristics, receptors and signaling pathways, mediating chemotaxis and adhesion of neutrophils, and its role in sepsis. Trend There has been plenty of studies on S100 proteins in chronic inflammation and cancer in the past decade. Now more and more studies are focusing on the proteins’ role in acute inflammation. The mechanism of S100A9 in sepsis is very complex. It has been proved that S100A8 and S100A9 have anti-oxidative and anti-inflammatory effect. Further research is needed to help understanding the protein better, and it may provide new prospective and direction for sepsis treatment.