Chronic kidney disease (CKD) is highly prevalent and a multiplier of cardiovascular disease (CVD) and cannot be completely explained by traditional Framinghan risk factors. Consequently, greater emphasis has been placed in nontraditional risk factors, such as inflammation, endothelial dysfunction, sympathetic overactivation, protein-energy wasting oxidative stress, vascular calcification, and volume overload. The accumulation of uremic toxins (and the involvement of genetic factors) is responsible for many of the clinical consequences of a condition known as uremia. In this brief paper, we discuss mechanisms involved in the vascular damage of CKD patients, aiming to point out that important factors beyond hypertension are largely responsible for endothelial activation and increased CVD risk, with potential impact on risk stratification and development of novel therapeutic options.