Artery stiffening, a biomechanical vascular property closely related to but separate from hypertension, is a strong and independent cardiovascular disease risk factor that also predicts end-organ failure. Decreased aortic compliance elevates the mechanical load on the myocardium, increases peripheral pulse pressure which damages high-flow organs such as the brain and kidneys, and contributes to atherosclerotic plaque formation and progression by altering mechanical stress signaling within the vessel wall. Many cardiovascular risk factors in addition to hypertension including aging, smoking, inflammation, and obesity have been associated with vessel stiffening. However, difficulties in assessing vascular stiffness as an independent variable in experimental models have made it challenging to determine the molecular mechanisms that drive its progression. Although decreases in aortic compliance were originally thought to be mediated by changes in extracellular matrix content and composition (ie, elastin degradation, collagen deposition), it has now become clear that the intrinsic mechanical properties of vascular smooth muscle cells (SMCs) also play a role.