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To postulate reasons as to why the benefits seen with novel therapies in animal models of sepsis fail to translate to the clinical setting.MEDLINE searches and relevant book chapters.Thousands of preclinical trials performed over more than five decades have failed to find more than a handful of drugs and techniques that significantly improve outcomes in clinical sepsis. We review current concepts surrounding the variety of animal models used today, ranging from simple models of acute toxemia to more complex models of abdominal sepsis. Differences between animal and human populations are also examined including species, age, comorbidity, and the use of supportive therapies. Finally, we examine differences between preclinical and clinical trial design, and the potential for experimental and publication bias.Animal models of sepsis are still too heterogeneous with regard to type of insult, duration, and supportive therapy to be regarded as representative of the human condition. Using standardized animal models may eliminate some of the differences between animal and human studies, allowing a greater degree of translation.