Platelets play a key role in hemostasis but are also responsible for the formation of pathogenic thrombi underlying the acute clinical manifestations of vascular atherothrombotic disease. Platelets are activated by multiple pathways, including adenosine diphosphate (ADP), thromboxane A(2) (TXA(2)), and thrombin, ultimately leading to formation of platelet-rich thrombi that occlude the arterial lumen, resulting in ischemia and cardiovascular events. Current oral antiplatelet agents inhibit the TXA(2) (aspirin [ASA]) and ADP platelet activation pathways (P2Y(12) ADP receptor antagonists) and have demonstrated clinical efficacy for the reduction of morbidity and mortality in patients with atherothrombotic disease. However, these agents are associated with residual risk for thrombotic events, bleeding risk, and variability in response. Thus, there is a strong clinical need for novel antiplatelet therapies that decrease the risk of thrombotic events without exposing patients to increased risk of bleeding. This review describes the clinical safety and efficacy of ASA and P2Y(12) ADP receptor antagonists, the limitations of current antiplatelet therapy, and novel therapies in development, including newer P2Y(12) ADP receptor antagonists and protease-activated receptor (PAR-1) inhibitors.