Tissue factor (TF) is abundantly present in atherosclerotic plaques and it is the primary source of TF that triggers the rapid activation of the coagulation cascade after plaque rupture. While much of this TF is associated with monocyte/macrophages and vascular smooth muscle cells, recent studies suggests TF-positive microparticles (MPs) are the most abundant source in plaques. Further, while intravascular TF is largely absent in healthy patients, cardiovascular disease patients have increased TF expression in circulating monocytes, which can result in increased levels of TF-positive MPs. This brief review describes how TF is the primary initiator of atherothrombosis and how TF-positive MPs may serve as a biomarker to identify patients at greater risk of forming an occlusive thrombus. In addition, currently used therapeutics, such as statins and inhibitors of the renin angiotensin system, may have additional benefits by reducing TF expression and subsequent thrombosis.