Atherosclerosis is a focal disease that develops preferentially where nonlaminar, disturbed blood flow occurs, such as branches, bifurcations, and curvatures of large arteries. Endothelial cells sense and respond differently to disturbed flow compared with steady laminar flow. Disturbed flow that occurs in so-called atheroprone areas activates proinflammatory and apoptotic signaling, and this results in endothelial dysfunction and leads to subsequent development of atherosclerosis. In contrast, steady laminar flow as atheroprotective flow promotes expression of many anti-inflammatory genes, such as Kruppel-like factor 2 and endothelial nitric oxide synthase and inhibits endothelial inflammation and athrogenesis. Here we will discuss that disturbed flow and steady laminar flow induce pro- and antiatherogenic events via flow type–specific mechanotransduction pathways. We will focus on 5 mechanosensitive pathways: mitogen-activated protein kinases/extracellular signal–regulated kinase 5/Kruppel-like factor 2 signaling, extracellular signal–regulated kinase/peroxisome proliferator–activated receptor signaling, and mechanosignaling pathways involving SUMOylation, protein kinase C-ζ, and p90 ribosomal S6 kinase. We think that clarifying regulation mechanisms between these 2 flow types will provide new insights into therapeutic approaches for the prevention and treatment of atherosclerosis.