Cardiovascular disease is both highly prevalent and exceedingly costly to treat. Several novel antiplatelet agents have been found to be effective in reducing the morbidity and mortality associated with cardiovascular disease. Understanding both the economic and the clinical implications of these novel therapies is particularly important. In this article, the results of published evaluations of the cost-effectiveness of oral antiplatelet strategies for use across a range of clinical conditions and treatment settings are reviewed. The results of these studies support the use of aspirin for primary prevention in high-risk patients and for secondary prevention in all patients with previous cardiovascular events. Although the optimal duration of dual antiplatelet therapy after an event remains uncertain, favorable cost-effectiveness estimates have been demonstrated for aspirin plus clopidogrel versus aspirin alone after a myocardial infarction or percutaneous coronary intervention. Moreover, prasugrel has been shown to be more cost-effective than clopidogrel for patients with an acute coronary syndrome and planned percutaneous coronary intervention. As novel antiplatelet agents emerge and existing agents are tested in different patient populations, the evaluation of the relative economic efficiency of these oral antiplatelet treatment strategies will continue to be instrumental to optimally inform clinical and health-policy decision-making.