1. Despite over half a century of intensive research, cardiovascular disease remains the leading cause of death world wide. Nevertheless, a number of risk factors for cardiovascular disease have been identified, such as hypertension and serum cholesterol, and therapies targeting such factors are effective in reducing cardiovascular and total mortality. Arterial stiffness is an additional independent risk factor for cardiovascular disease and strategies aimed at lowering arterial stiffness may be effective in reducing cardiovascular risk. However, in order to exploit fully the therapeutic potential of this approach, it is necessary first to understand the physiological and pathophysiological factors regulating the stiffness of the large arteries. 2. Until recently, stiffness was thought to depend largely upon structural components within the arterial wall, such as elastin and collagen and the distending pressure. However, we now recognize that arterial smooth muscle also regulates vessel stiffness and that a number of locally derived and circulating factors, including nitric oxide (NO), endothelin-1 and the natriuretic peptides, contribute to the short-term or functional regulation of large artery stiffness. Changes in the balance between these factors and, in particular, a reduction in NO production may well explain why conditions such as hypercholesterolaemia and diabetes are themselves associated with arterial stiffening before the development of manifest atherosclerosis. 3. The importance of smooth muscle in regulating arterial stiffness suggests that direct pharmacological manipulation of stiffness may be possible, thus providing novel therapeutic strategies to reduce cardiovascular risk. Furthermore, differences in the effect of existing drugs on larger artery stiffness may explain, in part, why some drugs produce better clinical outcomes than others.