Although anticoagulants have been in use for more than 80 years, heparin and vitamin K antagonists were the sole available options until recently. Although these agents revolutionized the prevention and treatment of thrombotic diseases, their use has been hampered by the necessity for coagulation monitoring and by bleeding complications resulting in part from their multiple sites of action. Owing to advances in basic science, animal models, and epidemiology, the arsenal of available anticoagulants has expanded in the past two decades. This evolution has yielded many novel compounds that target single coagulation enzymes. Initially, thrombin and factor Xa were targeted because of their critical roles in coagulation. However, attention has now shifted to compounds that target upstream reactions, particularly those catalyzed by factors XIIa and XIa, which are part of the contact system. This shift is predicated on epidemiological and experimental evidence suggesting that these factors are more important for thrombosis than for hemostasis. With the goal of developing a new class of anticoagulants associated with a lower risk of bleeding than currently available agents, dozens of drugs targeting the contact system are now in development. This article focuses on the rationale, development, and testing of these new agents with a concentration on those that have reached or completed phase 2 evaluation for at least one indication.