Despite major advances in antiplatelet therapies, recurrent cardiovascular events remain high after acute coronary syndrome. Furthermore, incremental benefits achieved in the reduction of atherothrombotic events have almost always been at the expense of hemorrhagic side effects. Thrombin is the most potent platelet activating factor known and it makes important interactions with the endothelium and vascular smooth muscle with proinflammatory, proatherogenic effects. Distinct from its activity within the coagulation cascade, thrombin mediates these effects via protease-activated receptor type 1 (PAR-1) in man. This review discusses the role of PAR-1 in the vasculature and the development of novel PAR-1 antagonists. These drugs may provide important antiatherothrombotic effects without attendant bleeding complications and could represent a major breakthrough for the treatment of cardiovascular diseases.