Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall and plays a central role in cell function and structure via managing several processes and contributes to the progress of atherosclerosis. It is a fact that interaction of blood flow and the endothelial surface is the critical interface for shear stressdependent mechanotransduction. Vascular endothelial cells are equipped with numerous receptors in order to “sense” and react to mechanical forces elicited by shear stress. The intracellular signal transduction pathways and specifically the activation of protein kinases, is the second important molecular event underpinning cellular reactions to extracellular stimuli. MAPKs, comprising ERK1/2, JNKs/stress-activated protein kinases (SAPKs), and p38s, are serine/threonine protein kinases with a prominent role in cell differentiation, growth, and apoptosis, by modulating the activity of downstream target proteins and various transcription factors, hence gene expression programs. Shear stress (nonlaminar or disturbed blood flow) plays an important role in atherosclerosis, where flow conditions are characterized by low or oscillatory shear stress. Atherosclerosis is promoted by decreased shear stress, as it is associated with a suppression of functions taking place on the vascular wall, such as eNOs production and endothelial cell repair. In the presence of systemic risk factors, there is an increased tendency for atherosclerotic plaque formation, which, once formed, further disrupt flow and forward growth of the fibroinflammatory lipid plaque. Targeted inhibition of many kinase types and subtypes is an immense research field as this may lead to novel therapeutic approaches to prevent atherogenesis.