Recombinant human activated protein C (APC) might be the first pharmacological intervention which decreases mortality in the course of severe sepsis. Surviving Sepsis Campaign guidelines have recommended the use of APC with grade B level of proof. During sepsis, the APC pathway serves as a major system for controlling thrombosis inhibiting thrombin formation, limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis. APC use was assessed in the course of severe sepsis 24 microg/kg/h for 96 hours with the aim of inhibiting coagulopathy and inflammation. The PROWESS trial included 1,690 patients and demonstrated a significantly decreased mortality in the treated group. Additional publications have clarified the characteristics of the included patients and tried to outline the potential benefits of APC. The results of ENHANCE, a multicenter open trial, have confirmed the trends reported in the PROWESS trial. Evidence supporting the efficacy of APC in the management of severe sepsis is clearly assessed. However, several issues remain unsolved and require to be addressed as the appropriate use of the drug and its place with other adjunctive therapies directed the sepsis process.