The recognition that thrombosis is fundamental to acute coronary syndromes (ACS) has inspired the development of novel therapies to inhibit platelet aggregation and thrombus formation. Several recent advances have been made in the management of patients undergoing percutaneous coronary revascularization and those with acute coronary syndromes to improve early and late clinical outcomes. The research efforts leading to these improvements in care have focused on antiplatelet and anticoagulant therapies coupled with early invasive treatment options. In particular, ongoing clinical trials seek to refine treatment strategies for patients relative to individual risk presentation and to determine the appropriate timing of the administration of antithrombotic therapies and revascularization. Simultaneous with attention toward improving efficacy with novel antithrombotic therapies, however, is an ongoing need to minimize bleeding risk. The purpose of this review is to provide a pathophysiologic rationale for the development of novel antiplatelet and antithrombin therapies in ACS and percutaneous coronary intervention, to examine the results of recent trials, and to present future directions for clinical investigation.