Diabetes mellitus is a major independent risk factor for acute coronary syndrome (ACS). In addition, diabetic patients with ACS suffer from increased mortality compared to their nondiabetic peers. Driven by multiple pathophysiological disturbances, such patients are predisposed to a proinflammatory, prothrombotic state, which may lead to plaque rupture. To counteract this more complex biology, several therapies and strategies have emerged, with some having unique preferential benefits in this population. Antiplatelet agents such as aspirin and clopidogrel have long been standard of care. Dose adjustment of these therapies remains the subject of continued research. Along with medical therapy, ACS diabetic patients preferentially benefit from primary percutaneous intervention compared to fibrinolysis. However, with advances in reperfusion techniques, the optimal strategy has yet to be determined. With these differences in ACS treatment responses, diabetic individuals may not just be a high-risk group, but may actually constitute a fundamentally different population, requiring dedicated clinical trials and individualized treatment regimens.