Antithrombotic therapy is a cornerstone of treatment for non-ST-segment elevation acute coronary syndromes, as demonstrated in numerous clinical trials. Long-term oral antiplatelet therapy targeting specific platelet activation pathways has demonstrated significant long-term benefits, whereas antithrombin use is limited to the acute setting. Despite proven efficacy of long-term dual oral antiplatelet therapy with aspirin and clopidogrel, residual morbidity and mortality is considerable. This may be partly due to incomplete inhibition of platelet activation with current agents and/or lack of long-term anticoagulant therapy. Improvements in patient outcomes could be achieved by developing agents that inhibit other platelet activation pathways or by adding new anticoagulants such as oral anti-IIa or anti-Xa agents for a prolonged period of time after the acute event. This review describes the rationale behind and the current status of the trials with new antithrombotic agents.