Severe sepsis, manifested by organ system dysfunction and/or shock, is the leading cause of death in patients in critical care units and is among the leading causes of death in the United States. New molecular biology techniques have allowed for a better understanding of the events that occur at the cellular and subcellular levels and produce this clinical syndrome. These same techniques have, for the first time, added treatment options aimed at blocking these interactions which, if unimpeded, may lead to an over-production of mediators that are toxic to the patient. The challenges remaining include the need for improvement in the early diagnosis of sepsis, clearer definitions of clinical stages of illness, and the need for careful clinical trials of the many potential therapeutic combinations.