Sepsis leads to an overwhelming inflammatory response of the host and is usually accompanied by well-known clinical symptoms (fever, tachycardia, leukocytosis, and so on) and the accompanying systemic inflammatory response syndrome (SIRS). Accordingly, most efforts to develop treatment strategies for sepsis have focused on those designed to counteract overactivation of the inflammatory system. Despite intensive research into identifying targets in sepsis, most of the resulting clinical trials have been based on experimental data and have resulted in no beneficial effects (i.e., survival). Recombinant activated protein C (APC) represents the first treatment that has led to restricted approval for use in sepsis in the USA and worldwide. This article reviews approaches to anti-inflammatory treatment in sepsis and provides an outlook into ongoing clinical trials as well as new treatments that have not yet been evaluated in the clinical setting.