The endothelium, a single layer of cells that lines all blood vessels, is the focus of intense interest in biomechanics because it is the principal recipient of hemodynamic shear stress. In arteries, shear stress has been demonstrated to regulate both acute vasoregulation and chronic adaptive vessel remodeling and is strongly implicated in the localization of atherosclerotic lesions. Thus, endothelial biomechanics and the associated mechanotransduction of shear stress are of great importance in vascular physiology and pathology. Here we discuss the important role of the cytoskeleton in a decentralization model of endothelial mechanotransduction. In particular, recent studies of four-dimensional cytoskeletal motion in living cells under external fluid mechanical forces are summarized together with new data on the spatial distribution of cytoskeletal strain. These quantitative studies strongly support the decentralized distribution of luminally imposed forces throughout the endothelial cell.