The global prevalence of diabetes mellitus (DM) continues to climb, and is accompanied by an increase in DM associated complications, most often manifesting as coronary heart disease. Platelet dysfunction has been implicated as a central contributor to the increased risk of coronary artery disease in patients with DM, and it is not surprising that the anti-platelet agent, clopidogrel, has been shown to have efficacy in both short and long term outcomes in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. However, accumulating data suggest a clinically relevant sub-optimal clopidogrel response in some patients with DM. The exact mechanism of these observations is not yet fully understood, but appears to be related to reduced concentrations of circulating clopidogrel active metabolite, with less variability in pharmacodynamic and clinical response suggested by the evaluation of newer P2Y(12) antagonists, such as prasugrel and ticagrelor. More research is needed to better understand both the pharmacology and clinical consequences of these observations.