Sepsis is a serious syndrome with a series of abnormalities caused by dysfunctional host response to infection. Toll-like receptor 4 (TLR-4) has been considered as a key regulator of inflammatory response and immune cell apoptosis in lipopolysaccharides (LPS) challenged models. However, in clinical trials, monoclonal antibodies of TLR-4 have not shown therapeutic effects as expected. Moreover, clinical trials based on immunotherapy by regulating inflammatory cytokines during the acute phase of sepsis have also failed. Recent evidence indicates that the fast-acting innate immune system plays a bigger role in blocking the fast progression of sepsis upon infection than the adaptive immune system. Consequently, the strategies for clinical management of sepsis should be shifted from targeting adaptive immune system to targeting innate immune system. In this review, we summarize our understanding of the role of TREML4 in sepsis, and highlight potential value of TREML4 in clinical management of sepsis. Further mechanistic studies on TREML4 such as the identification of its ligand will provide more clues on the development of novel and effective approaches to the prevention and therapy of sepsis.