Patients with chronic kidney disease have a higher burden of cardiovascular disease, which increases in a dose-dependent fashion with worsening kidney function. Traditional cardiovascular risk factors, including advanced age, diabetes mellitus, hypertension and dyslipidemia, have an important role in the progression of cardiovascular disease in patients who have a reduced glomerular filtration rate, especially in those with mild-to-moderate kidney disease. In patients with severe kidney disease, nontraditional or 'novel' risk factors, including inflammation, oxidative stress, vascular calcification, a prothrombotic milieu, and anemia, seem to confer additional risk. In this Review, we highlight factors that increase cardiovascular risk in patients with a reduced estimated glomerular filtration rate. In addition, we discuss therapeutic strategies for reducing cardiovascular risk in patients with kidney disease, whose unique atherosclerotic phenotype might require an approach that differs from traditional models developed in populations with normal kidney function. Therapeutic paradigms for patients with chronic kidney disease and cardiovascular risk factors must be evaluated in randomized trials, from which such patients have often been excluded.