The functions of platelets depend on their ability to interest with surface exposed at sites of tissue damage and then with one another after activation, thus aggregating into thrombi. This complex process, normally beneficial to arrest bleeding during hemostasis, may become a cause of catastrophic disease when it leads to thrombotic occlusion of atherosclerotic vessels curtailing arterial blood flow to vital organs. Fluid dynamic conditions modulate all aspects of platelet response to vascular injury. At higher levels of shear stress, encountered both in normal vessels during normal hemostasis or in pathological conditions of the vasculature during thrombosis, von Willebrand factor becomes the essential adhesive protein for both adhesion and aggregation. Two platelet membrane receptors, the glycoprotein complexes Ib-IX-V and IIb-IIIa (integrin alpha IIb beta 3), mediate the von Willebrand factor function in a coordinate and synergistic manner, each contributing unique biomechanical properties to support thrombus formation. The developing understanding of the structure and mechanism of action of the key adhesive domains of von Willebrand factor, as well as of their cognate cellular and extracellular binding sites, will provide solid pathophysiological foundation for the evaluation of novel anti-thrombotic strategies.