Atherosclerosis preferentially develops at branches and curvatures of the arterial tree, where blood flow is disturbed from a laminar pattern, and wall shear stress is non-uniform and has an irregular distribution. Vascular endothelial cells (ECs), which form an interface between the flowing blood and the vessel wall, are exposed to blood flow-induced shear stress. There is increasing evidence suggesting that laminar blood flow and sustained high shear stress modulate the expression of EC genes and proteins that function to protect against atherosclerosis; in contrast, disturbed blood flow and the associated low and reciprocating shear stress upregulate proatherosclerotic genes and proteins that promote development of atherosclerosis. Understanding of the effects of shear stress on ECs will provide mechanistic insights into its role in the pathogenesis of atherosclerosis. The aim of this review article is to summarize current findings on the effects of shear stress on ECs, in terms of their signal transduction, gene expression, structure, and function. These endothelial cellular responses have important relevance to understanding the pathophysiological effects of altered shear stress associated with atherosclerosis and thrombosis and their complications.