Coronary artery disease develops and progresses over decades with lipid incorporation and coalescence into the arterial wall, leading to recurrent plaque disruption, thrombosis, and organization into fibromuscular lesions. The role of thrombin in arterial thrombosis is documented by observations that specific thrombin inhibition can completely prevent intraluminal mural thrombus in vivo, even though other factors that activate platelets are not inhibited. Platelet-rich thrombi associated with deep injury have a high thrombin content and require blood levels of specific thrombin inhibition with hirudin that are eight to 10 times those required to prevent thrombi associated with lesser injury or stasis. Total prevention of mural thrombus in deeply injured arteries is impossible with aspirin or conventional antithrombotic therapy, which can reduce occlusive thrombus. Thus, conventional antithrombotic therapies can reduce clinical events but are not effective in reducing progression of coronary artery disease. Whether newer antithrombins that can totally prevent mural thrombus after deep injury can be developed and administered orally and chronically without high risk of bleeding and will be able to reduce progression of coronary artery disease is unknown. Lesion growth, vascular injury, acute coronary syndromes, and principles of thrombus formation on ruptured plaque are discussed elsewhere in this issue. This article extends these findings and discusses the prevention and treatment of mural thrombosis, the pivotal role of thrombin in arterial thrombosis, and antithrombotic therapy for the prevention and the progression of coronary artery disease.