Diabetes mellitus patients are characterized by enhanced platelet reactivity which exposes them to an increased risk of atherothrombotic events in the setting of acute coronary syndromes or percutaneous coronary interventions. Although aspirin and clopidogrel, used either solely or in combination, are associated with improved clinical outcomes in high-risk patients, diabetics patients treated with antiplatelet agents remain at higher risk of recurrent ischemic events. Recent laboratory findings suggest that this observation may be related to a reduced responsiveness or 'resistance' to these agents. In this chapter the efficacy of currently available oral antiplatelet agents in preventing ischemic events is reviewed. In addition, the antiplatelet 'resistance' phenomenon in the diabetic population and its impact on clinical outcomes is summarized. Finally, future developments in the field directed towards individualized treatment strategies and novel antiplatelet agents are examined.