Historically, the use of oral anticoagulants in acute coronary syndromes (ACS) has been controversial. Several prospective trials have shown that vitamin K antagonists (VKAs), such as warfarin or dicoumarol, reduce recurrent ischemic events but with a concomitant increased risk of bleeding. Other trial data have shown a neutral or net negative effect. Regardless, these prior observations are not readily transposable to contemporary practice where many ACS patients receive dual antiplatelet therapy and undergo cardiac catheterization and percutaneous coronary intervention. Because recurrent ischemic events continue to occur following index ACS presentation despite evidence-based practice and knowing the limitations of current oral anticoagulation strategies with VKA, the endeavor continues to find a more effective anticoagulant with predictable, dose-proportional pharmacokinetics, and minimal interactions with food and drugs. We review novel, emerging classes of anticoagulants that focus on specific targets in the coagulation cascade with the aim of improving long-term net clinical outcomes.