Evidence suggests that aortic stiffness may antedate and contribute initially to the development of hypertension and cardiovascular risk (CVR). In treated hypertensive patients, both diabetes and end-stage renal disease (ESRD) are comorbid conditions associated with increased aortic stiffness and high CVR. Thus, the pathophysiological relationship between aortic stiffness, blood pressure (BP) and CVR may have clinical implication in the management of hypertension. In patients with diabetes or ESRD, aortic stiffness is a significant predictor of CVR, independently of BP control. The hallmark of accelerated aortic stiffening in these patients associates the presence of vascular calcification, which is considered as a time-dependent process. Aortic stiffness represents a marker of structural but also functional arterial damage associated with increased pressure pulsatility. Carotid–femoral pulse wave velocity (cf-PWV), as a marker of aortic stiffness, may provide a readily available information for the effectiveness of risk reduction strategies. SBP, hyperglycemia and progressive alteration of renal function are considered as determinants of accelerated aortic stiffening. These findings suggest that earlier and intensive treatment of glycemia and BP could be important to limit or even reverse stiffening process. In patients with ESRD, more specific and potentially modifiable kidney disease-related parameters such as phosphocalcic disorders and vitamin K deficiency, appear correlated with aortic calcification and cf-PWV. An important and recent finding is that the magnitude of longitudinal increase in cf-PWV may represent a clinically pertinent surrogate for cardiovascular events. Aortic stiffness may be, thus, considered as an intermediate marker to monitor effectiveness of preventive strategies in these high-risk patients.