Hypertension in older persons is characterized by increased systolic blood pressure, and isolated systolic hypertension (ISH) is the most common type of hypertension in this population. It is thought that ISH results from age-associated vascular stiffening and reduced compliance that can be revealed and quantified by analysis of arterial pressure waveforms. Evaluation of pulse wave velocity and other related measures has shown that arterial stiffness increases with advancing age and other cardiovascular (CV) risk factors including hypertension, the metabolic syndrome, diabetes, obesity, hypercholesterolemia, and elevated C-reactive protein. Many of these relationships have been demonstrated in patients without clinical CV disease and are independent of patient age. Arterial stiffness is significantly and independently associated with both target organ damage and increased risk for CV morbidity and mortality. The mechanisms underlying age- and disease-related arterial stiffening are not fully understood. However, assessment of changes in gene expression associated with increased arterial stiffness and gene polymorphisms that increase the risk for vascular stiffening suggests that components of the renin–angiotensin system, matrix metalloproteinases, intracellular signaling, and extracellular matrix components may all be involved in this process. Interventions aimed at these targets may reduce vascular stiffness, lower systolic blood pressure, decrease the prevalence of ISH, and improve outcomes for patients (particularly older patients) with hypertension or other CV conditions.