A traditional perspective of arterial thrombosis begins with vessel wall injury and exposure of subendothelial proteins, including collagen and tissue factor, to circulating cellular and non-cellular components. Adhesion and activation of platelets, mediated by their interaction with von Willebrand protein and collagen, respectively, coupled with tissue factor-mediated activation of coagulation proteins, results in thrombin generation and fibrin formation. While this time-honored paradigm remains firm and soundly based, emerging evidence suggests that arterial thrombosis is much more complex and dynamic than originally believed. Several novel triggers, templates and facilitators, such as cell-free nucleic acids, histones, DNA-histone complexes, polyphosphates, and microvesicles have recently been identified and require inclusion in the expanding universe of thrombosis as a dominant phenotype of human disease. Because these mediators appear to have modest if any effect on physiologic hemostasis, they likely represent acquired and disease or condition-dependent processes that are highly attractive targets for pharmacologic intervention.