Despite the efficacy of intravenous glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention and those presenting with acute coronary syndromes, the application of oral glycoprotein IIb/IIIa inhibition to the chronic management of coronary artery disease has not met with the same success. To explain these results, factors related to dosing, and inadequate inhibition or activation of platelet pro-coagulant activity have been recently suggested. However, although the disparity between intravenous and oral glycoprotein IIb/IIIa experience remains largely enigmatic, the discordant effect on ischemic endpoints observed within the phase III oral glycoprotein IIb/IIIa inhibitor trials potentially implicates a mechanism unrelated to platelet function.