Contemporary management of acute coronary syndromes (ACS) has evolved to include rapid revascularization, potent antithrombotic, and antiplatelets, all of which reduce the risk of ischemic complications. Despite these advances, recurrent ischemic and bleeding event rates are still substantial. This increased risk post-percutaneous coronary intervention (PCI) has been the seminal event leading to recent clinical trials evaluating more potent antiplatelet drugs (prasugrel, ticagrelor, and protease-activated receptor-1 [PAR-1] inhibitors) and novel oral anticoagulants (NOAC). Ideally, an effective anticoagulation regimen adequately reduces the incidence of recurrent ischemia and limits iatrogenic bleeding. In this review, we will discuss the advances in ACS pharmacotherapy, review the recent trials evaluating these drugs, and discuss the major dilemmas in interpreting and implementing their findings.