A healthy aorta exerts a powerful cushioning function, which limits arterial pulsatility and protects the microvasculature from potentially harmful fluctuations in pressure and blood flow. Large-artery (aortic) stiffening, which occurs with aging and various pathologic states, impairs this cushioning function, and has important consequences on cardiovascular health, including isolated systolic hypertension, excessive penetration of pulsatile energy into the microvasculature of target organs that operate at low vascular resistance, and abnormal ventricular-arterial interactions that promote left ventricular remodeling, dysfunction, and failure. Large-artery stiffness independently predicts cardiovascular risk and represents a high-priority therapeutic target to ameliorate the global burden of cardiovascular disease. This paper provides an overview of key physiologic and biophysical principles related to arterial stiffness, the impact of aortic stiffening on target organs, noninvasive methods for the measurement of arterial stiffness, mechanisms leading to aortic stiffening, therapeutic approaches to reduce it, and clinical applications of arterial stiffness measurements.