Endothelial cells (ECs) lining blood vessels have a variety of functions and play a critical role in the homeostasis of the circulatory system. It has become clear that biomechanical forces generated by blood flow regulate EC functions. ECs are in direct contact with blood flow and exposed to shear stress, a frictional force generated by flowing blood. A number of recent studies have revealed that ECs recognize changes in shear stress and transmit signals to the interior of the cell, which leads to cell responses that involve changes in cell morphology, cell function, and gene expression. These EC responses to shear stress are thought to play important roles in blood flow-dependent phenomena such as vascular tone control, angiogenesis, vascular remodeling, and atherogenesis. Much research has been done on shear stress sensing and signal transduction, and their molecular mechanisms are gradually becoming understood. However, much remains uncertain, and many candidates have been proposed for shear stress sensors. More extensive studies of vascular mechanobiology should increase our understanding of the molecular basis of the blood flow-mediated control of vascular functions.