It is increasingly accepted that arterial stiffening is associated with and probably causes damage of small vasculature in perfused organs, inducing or perpetuating hypertension, stroke, chronic kidney disease and Alzheimer disease. Artery stiffening, manifested as increased elastic modulus and compliance of arteries due to aging, diabetes or hypoxia, also predicts pharmacological outcomes in a variety of small blood vessel dysfunction. Despite clear clinical evidence, the contribution of artery stiffening to changes in blood flow environments and consequent vascular responses remains elusive. Our recent studies have revealed the important role of arterial elasticity in altering pressure and flow pulsatility as well as dynamic profiles of vessel wall shear stress, which led to pro-inflammatory and vasoconstrictive responses from vascular cells through cytoskeleton-mediated mechano-transduction. In addition to increasing flow pulsatile stress, reduced hydraulic cushion function of elastic arteries also changes flow energy expenditure in the vasculature. Improved understanding of artery stiffening-induced flow changes and consequent vascular cell mechanosensing mechanisms will greatly assist the development of novel therapies of associated diseases.