Platelet activation, achieved through a variety of surface receptors and biochemical mediators, represents a key event in the pathogenesis of atherothrombosis and its clinical manifestations. The major pathways involved in platelet activation are triggered by thromboxane A(2), adenosine diphosphate and thrombin, with the latter being the most potent of these agonists. Despite the effective inhibition of the first two pathways with aspirin and several generations of P2Y(12) receptor antagonists, respectively, the recurrence of ischaemic events in patients with atherothrombosis remains high. In addition, there is a growing concern over the safety profile of increasingly powerful antiplatelet drugs in terms of bleeding, which has tempered expectations of newly developed compounds. Thrombin receptor antagonists are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preliminary data indicate that these compounds may have the potential to improve ischaemic outcomes without significantly increasing the bleeding liability. Currently, two agents of this class are under clinical development: vorapaxar (previously known as SCH 530348) and E-5555. In this review we discuss this novel class of antiplatelet agents, focusing in particular on their therapeutic potential.