Sepsis can be defined as a systemic inflammatory response syndrome occurring in the presence of an infectious source. Over the past 25 years, numerous guidelines have been established to clarify definitions and improve the overall management of clinical sepsis. In light of these multiple paradigm shifts, this review attempts to summarize the innate immunologic alterations that manifest during sepsis, establish and compare mouse models of sepsis with the clinical course, and discuss the authors’ views on additional elements that should be considered in modeling and predicting clinical sepsis from the standpoint of a basic research setting.