Sepsis remains one of the leading causes of mortality in critically ill patients. Increased insight into the complexities of this disease process has resulted in the targeting of various aspects of the inflammatory response as offering potential therapeutic benefits. There have been encouraging results in the past few years. Some of the tested agents have been shown to improve mortality rates in large randomized controlled trials involving patients with severe sepsis. In this article, we discuss the positive and negative results of trials in this field; some of the possible reasons for the negative results are examined, and directions for the future are suggested.