Atherosclerosis initiates at predictable focal sites near arterial branches and curves, where blood flow is disturbed and shear stress is complex. Endothelial shear stress is the tangential stress derived from the friction of the flowing blood on the endothelial surface of the arterial wall. It is a key factor in modulating endothelial cell gene expression and vascular development and remodeling. Increasing evidences suggest that shear stress patterns have a strong relationship with atherosclerotic features. Moreover, variations in the local artery geometry during atherogenesis further modify flow shear stress characteristics, which contribute to the rupture site at the plaque upstream. In this study, we summarize the mechanistic evidences that associate shear stress patterns with determined atherosclerotic plaque features. An enhanced understanding of the relationship and pathophysiological function of shear stress patterns in atherosclerotic plaque features is essential, which may provide early prediction of clinical risk and guide individualized treatment strategies. In the current review, we analyzed the function of shear stress on the determination of atherosclerotic lesion and provided an update on the mechanotransduction of shear stress, gene expression regulation, and atherosclerotic plaque development and rupture.