Protein C, a vitamin K-dependent serine protease zymogen that circulates in plasma, is converted by limited proteolysis to activated protein C (APC) by the thrombin-thrombomodulin complex. APC exerts anticoagulant, antiinflammatory, cytoprotective, and antiapoptotic activities. Recombinant APC therapy reduces mortality in severe sepsis patients. This review summarizes data from clinical observations, from in vitro studies, and from animal models of focal ischemic injury that provide a compelling rationale for clinical trials of APC for ischemic stroke.