Activated platelets play a crucial role in the pathogenesis of atherothrombotic disease and its complications. Even under treatment of antiplatelet drugs, such as acetylsalicylic acid and P2Y12 antagonists, morbidity and mortality rates of thromboembolic complications remain high. Hence, the therapeutic inhibition of protease-activated receptor (PAR)-1, which is activated by thrombin, is a novel promising approach in antiplatelet therapy. Recent data suggest that PAR-1 is mainly involved in pathological thrombus formation, but not in physiological hemostasis. Therefore, PAR-1 inhibition offers the possibility to reduce atherothrombotic events without increasing bleeding risk. So far, two emerging PAR-1 antagonists have been tested in clinical trials: vorapaxar (SCH530349; Merck & Co., Whitehouse Station, NJ, USA) and atopaxar (E5555; Eisai, Tokyo, Japan). Although in TRA-CER vorapaxar showed an unfavorable profile for patients with acute coronary syndrome in addition to standard therapy, it revealed promising results for patients with prior myocardial infarction in TRA 2P-TIMI50. Depending on the status of clinical approval, vorapaxar might be an option for patients with peripheral arterial disease to reduce limb ischemia. The second PAR-I antagonist, atopaxar, tended towards reducing major cardiovascular adverse events in acute coronary syndrome patients in a phase II trial. However, although statistically not significant, bleeding events were numerically increased in atopaxar-treated patients compared with placebo. Furthermore, liver enzymes were elevated and the relative corrected QT interval was prolonged in atopaxar-treated patients. Currently, the development of atopaxar by Eisai is discontinued. The future of this novel class of antithrombotic drugs will depend on the identification of patient groups in which the risk-benefit ratio is favorable.