Platelets play an important role in the pathogenesis of thrombosis, the most common cause for the development of acute coronary syndromes such as complications occurring during percutaneous coronary intervention. Platelets act with a multiple step mechanism, in which different surface molecules are involved representing important therapeutic targets of antiplatelet agents. Despite clopidogrel efficacy which has been demonstrated in several studies, recurrent ischemic events remain considerably high in patients on treatment due to low clopidogrel responsiveness, a phenomenon influenced by environmental, clinical, and genetic factors. New P2Y12 blockers such as prasugrel and ticagrelor have been successfully introduced in clinical practice, whereas cangrelor, with a rapid offset and reversible platelet inhibition, may represent a useful bridging therapy in patients undergoing surgery. Moreover, the simultaneous inhibition of thrombin platelet aggregation by protease-activated receptor inhibitors may be an adjunctive approach in patients with coronary artery disease.