Atherosclerosis is a progressive disease characterized by the accumulation of lipids in medium to large sized arteries. Atherothrombosis is a term used to describe formation of a thrombus after rupture of an atherosclerotic plaque. Thrombosis can lead to myocardial infarction and stroke. Risk factors for atherosclerosis include hyperlipidemia, diabetes, smoking and hypertension all of which increase tissue factor (TF) expression. High levels of TF are present in atherosclerotic plaques due to expression by macrophages and vascular smooth muscle cells and the presence of cell-derived TF-positive microvesicles (MVs). In addition, hyperlipidemia leads to the formation of oxidized LDL, which induces TF expression in circulating monocytes and the release of TF-positive MVs. The major source of TF that drives thrombosis after plaque rupture is TF within the plaque. However, TF in the blood on monocytes and MVs may also contribute the thrombosis. Inhibition of the TF/factor VIIa complex is unlikely to be an effective strategy to reduce atherothrombosis due the essential role of the complex in hemostasis. However, selective blockade of pathologic TF without affecting protective TF may be effective in reducing atherothrombosis. For instance, statins have been shown to reduce TF expression in the plaque and in circulating monocytes, which would be expected to reduce thrombosis. Further studies are needed to determine safe strategies to reduce pathologic TF expression and atherothrombosis.