Sepsis describes a complex clinical syndrome that results from the host inability to regulate the inflammatory response against infection. Despite more than 20 years of extensive study, sepsis and excessive systemic inflammatory response syndrome (SIRS) are still the leading cause of death in intensive care units. The clinical study of sepsis and new therapeutics remains challenging due to the complexity of this disease. Therefore, many animal models have been employed to investigate the pathogenesis of sepsis and to preliminarily test potential therapeutics. However, so far, most therapeutics that have shown promising results in animal models failed in human clinical trials. In this chapter we will present an overview of different experimental animal models of sepsis and compare their advantages and disadvantage. The studies in animal models have greatly improved our understanding about the inflammatory mediators in sepsis. In this chapter we will also highlight the roles of several critical mediators including TNF-α, IL-1β, IL-6, chemokines, substance P, hydrogen sulfide and activated protein C in animal models of sepsis as well as in clinical studies.