A unique feature of the vascular system is that the natural environment is mechanically dynamic as a result of blood flow. Major hemodynamic forces include frictional wall shear stress, hydrostatic pressure, and circumferential stress. There is ample evidence that hemodynamic forces play a key role in the maintenance of vascular integrity and the guidance of vascular remodeling, as well as the development of vascular diseases. Vascular endothelial cells line the inner wall of blood vessels to separate circulating blood and other vascular tissues, and they are believed to act as a sensor of the local hemodynamic environment. This lecture will address what is currently known regarding the flow-induced mechanotransduction in vascular endothelial cells and the ensuing changes in endothelial cell function. Special emphases will be placed on those related to the development of atheroscelerotic lesions and vasoocclusive crises in sickle cell anemia.