Despite advances in supportive care and medical technology, the mortality rate from SIRS/sepsis remain high. Over the last 20 years, prevailing thought has attributed much of the morbidity and mortality of sepsis to an overexuberant host inflammatory response to bacterial products. In preclinical studies, agents designed to limit this host pro-inflammatory response showed promising effects, prompting numerous clinical trial. The purpose is to review the lessons learned from large clinical trials in SIRS/sepsis over last ten years.