Frequently used experimental models of sepsis include cecal ligation and puncture, ascending colon stent peritonitis, and the i.p. or i.v. injection of bacteria or bacterial products (such as LPS). Many of these models mimic the pathophysiology of human sepsis. However, identification of mediators in animals, the blockade of which has been protective, has not translated into clinical efficacy in septic humans. We describe the shortcomings of the animal models and reasons why effective therapy for human sepsis cannot be derived readily from promising findings in animal sepsis.