Acute coronary syndrome is the number one killer in the industrialized world and, as such, continues to be one of the most well-studied disease states in all of medicine. Advancements in antiplatelet therapies for use in patients undergoing percutaneous coronary intervention have improved outcomes dramatically. However, a proportion of patients on long-term antiplatelet therapy continue to have cardiovascular events. Resistance to antiplatelet drugs may explain some of these events and this topic has become one of major interest and rapid evolution. This review describes the pathogenesis of acute coronary syndromes, outlines the evidence behind the use of the available antiplatelet agents, and examines the current data surrounding antiplatelet resistance.