Therapeutic strategies to prevent cardiovascular disease are based on the ability of the intervention to reduce specific risk factors and subsequent end-organ damage, implying that these factors are causally involved in the pathogenesis of the disease. In subjects with normal kidney function, the control of classic, Framingham-type, risk factors (blood pressure, glycemia, lipids, smoking) reduces impressively the burden of cardiovascular disease. In chronic kidney disease (CKD), prevention is based on similar strategies in general and on reduction of proteinuria (blockade of the renin-angiotensin-aldosterone system [RAAS], salt restriction) in particular. Although several nontraditional risk factors are recognized already in early stages of CKD (stages 1 and 2), they become more prominent in stages 3 to 5, most likely responsible for a different pathology. In fact, cardiovascular and all-cause mortality increase dramatically from CKD stage 3b (glomerular filtration rate < 45 mL/min/1.72 m2) to stage 5, and the pattern of cardiac and vascular damage changes profoundly. It appears that arteriosclerosis is recognized more often than atherosclerosis, and left ventricular hypertrophy or cardiac fibrosis is prominent. Randomized controlled trials in advanced CKD and stage 5D using strategies targeting classic risk factors indicate that treatments are not as effective as in subjects with normal kidney function. Whether late stages of CKD or a risk pattern dominated by nonclassic risk factors need a different or an additional approach or whether we can use biomarkers to detect the turning point is currently a matter of intense discussion among nephrologists and clinical scientists.