Stroke and myocardial infarction are leading causes of death and disability worldwide. Typically, these events are triggered by the rupture or erosion of "vulnerable" atherosclerotic plaque, a phenomenon termed atherothrombosis.Three platelet activation pathways are presumed to be particularly important in the genesis of atherothrombosis and are triggered by 1) cyclo-oxygenase (COX)-1 mediated thromboxane A2 (TXA2) synthesis and activation via the TXA2 receptor, 2) adenosine diphosphate (ADP) via the P2Y12 receptor, and 3) thrombin via the protease activated receptor (PAR)-1.Despite the efficacy of aspirin and of a growing family of P2Y12 receptor antagonists on the first 2 pathways, major cardiovascular events continue to occur in patients with coronary and cerebrovascular disease, suggesting that thrombin-mediated platelet activation may contribute to these adverse events.Recently, a novel class of antiplatelet agents able to inhibit thrombin-mediated platelet activation has been developed, PAR-1 inhibitors. In this chapter, we will discuss the rationale underlying the development of this novel class of agents focus on the two drugs in the most advanced stages of development: vorapaxar (SCH530348) and atopaxar (E5555).