The contribution of thrombosis to the natural history and clinical expression of advanced atherosclerotic coronary artery disease is well established. Less well understood is the biochemical and pathobiological distinction between normal hemostasis and thrombosis as the proximate cause of acute coronary syndrome. In this article, we summarize an evolving area of interest within the field of antithrombotic therapy--the contact system and the intrinsic pathway of coagulation, focusing our discussion on factors XI, XII, and IX to include their biochemical properties, relationship to arterial thrombosis phenotypes, and rational for future investigation of targeted pharmacotherapy.