The leading cause of mortality in industrialized societies is sudden cardiac death. Almost half a million people die each year in the United States from myocardial ischemia and infarction leading to ventricular fibrillation. These phenomena result from severe coronary artery disease due to atherosclerosis with acute mural thrombosis causing occlusion, which serves as the terminal event. Various studies have found evidence of fresh coronary artery mural thrombosis in 74 to 94 percent of patients undergoing autopsies shortly after death due to acute myocardial infarction. Not all thrombi are occlusive, but vasospasm associated with fresh injury to the diseased vessel may be sufficient with developing new thrombus to block blood flow. Because platelets are a major constituent of newly formed thrombi and contribute significantly to vaso-occlusive disease, it is important to understand basic aspects of their function. Such studies may lead to measures that prevent vascular disease and thrombosis. This chapter has described ultrastructural features of platelet-vessel wall interaction. Adhesion, spreading, secretion, and aggregate or thrombus formation have been emphasized. The findings of current studies indicate strong similarities between platelet-vessel wall interactions and the response of platelets to other surfaces. Also, platelet transformations observed during aggregate formation in suspension are identical to physical changes in thrombi on damaged vessels. The similarities are much more impressive than the differences. Therefore, the role of platelets in arterial thrombosis can be understood best as an extension of their hemostatic function. An advantage of this observation is that understanding basic mechanisms of platelet function in hemostasis can lead to solution of the problems presented by platelet involvement in thrombosis. The disadvantage is that agents used to prevent thrombosis can place the hemostatic mechanism in jeopardy. Finding the answer to this paradox will occupy our attention for years to come.