Physicians are aware of the profound impact of oral antiplatelet therapy for secondary prevention of acute coronary syndrome (ACS), transient ischemic attack, and noncardioembolic stroke. Numerous clinical studies have compared the benefits of aspirin (ASA) alone with those of combination therapy with extended-release dipyridamole or with those of clopidogrel, with or without ASA, for secondary stroke prevention; and of ASA monotherapy compared with ASA plus clopidogrel combination therapy for secondary prevention in various ACS populations. More recently, ASA plus prasugrel has been compared with ASA plus clopidogrel in a high-risk ACS population. However, given the different treatment modalities and methods used in the various trials, it is difficult to make generalizations as to which therapy is most effective with the lowest risk of bleeding. Further complicating physician’s decision making are cost considerations, particularly with the newer oral antiplatelet agents, which are considerably more expensive than ASA. This review provides a brief overview of the clinical data on each of the currently marketed oral antiplatelet agents and the available data on cost-effectiveness for the secondary prevention of ACS, transient ischemic attack, and noncardioembolic stroke.