There is increasing evidence that von Willebrand factor (VWF), an adhesive multimeric protein that has an important function in primary hemostasis and as a carrier of factor VIII, has a pivotal role in thrombogenesis. In fact, while the presence in plasma of unusually large VWF multimers due to a congenital or acquired deficiency of a VWF-cleaving metalloprotease has been implicated in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), high plasma levels of VWF have been associated with a slightly increased risk of arterial thrombosis. With regard to the association between VWF and venous thrombosis, clear conclusions cannot yet be drawn from the conflicting published data. Patients with von Willebrand disease, an inherited hemorrhagic disorder, may also paradoxically experience thrombotic events as a result of interactions among multiple prothrombotic risk factors. After a description of the structure and physiology of VWF, all these aspects are discussed in the present review.