Sepsis is a severe systemic inflammatory response syndrome, and is common in the patients with infection, extensive burn injury and major surgery. As it may cause multiple organ dysfunction and septic shock, it is always accompanied with high mortality and poor prognosis. Currently there’s no effective medication available for treatment of sepsis. During the process of killing bacteria, the classical antibiotics lead to release of a large quantity of proinflammatory cytokines, such as lipopolysaccharide, which exacerbates the malfunction of immune system. Furthermore, the growing number of multiresistant bacteria present a new challenge to the management of sepsis. Antimicrobial peptides (AMPs) are small, cationic, and amphipathic peptides with broad-spectrum microbicidal activity against bacteria, fungi and viruses. In addition, they also can neutralize endotoxin and suppress inflammatory cascade through multiple immunomodulation, which potentially serves as a promising alternative approach for sepsis treatment. This review briefly summarizes the progress of AMPs in the treatment of sepsis as well as the relevant mechanisms.