Cardiovascular disease is a leading cause of death and pathologic coagulation plays an integral role in the development, propagation, and intervention of cardiovascular disease. The 2 classic anticoagulants, heparin and vitamin K antagonists, though having served humanity for nearly a century, are both inconvenient and nonspecific. Through both direct and indirect roles, thrombin is essential to coagulation, and makes for a very attractive target in medical intervention of pathologic thrombosis. This article will review the nature of direct thrombin inhibitors, current indications, and ongoing trials.