Great strides in interventional pharmacotherapy have been made over the past few decades, virtually all focused on optimizing peri-PCI antithrombotic therapy in order to reduce thrombotic complications. Our understanding of the role of platelets and of antiplatelet therapies in this process continues to evolve. Today, dual or even triple antiplatelet therapy has become standard of care at the time of PCI followed by dual therapy long-term in the majority of patients. However, currently available oral regimens are hampered by limitations including the need to initiate treatment at least a few hours before the procedure to achieve maximum benefit and the safety issues surrounding irreversible platelet inhibition in the uncommon, but not rare situations when a patient requires surgical revascularization. These limitations have led to the suboptimal "real-world" utilization of these proven agents and have fostered the development of a wide variety of alternative platelet inhibitors with theoretical, but still unproven clinical benefits. There are ample clinical data that strongly support the use of aspirin and clopidogrel in virtually all patients undergoing a PCI today. This review will highlight these data as well as emphasize the gaps in our understanding. (c) 2007 Wiley-Liss, Inc.