Acute inflammatory events, such as those that occur in sepsis, lead to dysregulation of the coagulation cascade. The hemostatic imbalance in sepsis, characterized by the excessive activation of procoagulant pathways and the impairment of anticoagulant activity, leads to disseminated intravascular coagulation and results in microvascular thrombosis, tissue hypoperfusion and, ultimately, multiple organ failure and death. Furthermore, natural anti-inflammatory mechanisms of the endogenous anticoagulants are diminished by the impaired coagulation. Supportive strategies aiming at inhibiting activation of coagulation and inflammation by treatment with exogenous anticoagulants have been found to be beneficial in experimental and initial clinical studies. This review summarizes the available experimental and clinical data regarding the interaction between coagulation and inflammation, focusing on the two anticoagulants which are in clinical use, antithrombin and activated protein C. Identification of the different biological mechanisms of the two endogenous anticoagulants might help to determine target patient populations as well as to develop new anticoagulant analogs that differ in there respective effects in coagulation and inflammation.