Ceiling effect with respect to antiischemic efficacy and elevated bleeding risk associated with current potent antiplatelet therapy with a P2Y12 receptor inhibitor and aspirin stimulated the research to target other important platelet thrombin receptor, protease-activated receptor (PAR)-1. Among several PAR-1 receptor inhibitors developed, only vorapaxar is indicated for treatment. It is an orally administered agent that significantly inhibits PAR-1 with high affinity. Due to the slow dissociation rate, it has a delayed offset of pharmacodynamic properties. Although vorapaxar when added to standard medical care was associated with an elevated risk of bleeding, net clinical benefit was favorable in patients with a history of acute myocardial infarction or peripheral artery disease. Based on these favorable results, vorapaxar was approved as an adjunctive therapy to standard care antiplatelet treatment regimens for secondary prevention in the latter patient population. Rapid and reversible inhibition of PAR-1 signaling by a parenteral strategy with lower bleeding risk is ideal in the setting of unanticipated surgery. PZ-128, a pepducin, is a lipidated peptide targeting the cytoplasmic surface of the PAR-1 receptor. Early-stage human studies demonstrated a significant, and rapid onset and offset of PAR-1 inhibition associated with PZ128. Since PAR-1 inhibition was associated with elevated bleeding risk and limited anti-ischemic efficacy, research focus has been shifted towards another platelet thrombin receptor, PAR-4. Animal and early human studies indicate that BMS986120, a PAR-4 receptor inhibitor, is associated with potent and selective inhibition of PAR-4 receptor when added to a P2Y12 receptor inhibitor with minimum influence on bleeding. However, further large-scale studies are needed to define its precise role and benefits in patients with arterial diseases.