Patients with diabetes mellitus have increased atherothrombotic risk and elevated rates of recurrent cardiac events, which may be in part attributable to abnormalities of platelet function resulting in increased platelet reactivity. Despite improved clinical outcomes with an antiplatelet strategy of aspirin plus clopidogrel in patients with acute coronary syndrome (ACS), diabetic patients continue to experience relatively high rates of adverse events during follow-up. Thus, strategies using more potent antiplatelet drugs are warranted in diabetic patients with ACS, especially in the presence of an increased coronary angiographic risk profile. The relative benefit of prasugrel has been described as higher in diabetic vs. nondiabetic patients, without increase in the bleeding risk, whereas a reduction in ischemic events was similar with ticagrelor in patients with and without diabetes. Glycoprotein IIb/IIIa inhibitors are indicated in high-risk patients with ACS, but diabetic patients do not benefit from routine administration of such agents.