Summary Patients with end-stage renal disease are characterized by extensive vascular calcification and high cardiovascular disease (CVD) risk. Calcification in end-stage renal disease patients represents at least two distinct pathologic processes. Calcification within the tunica intima frequently is associated with lipid-laden, flow-limiting atherosclerotic plaques. These appear as spotty areas of calcification interspersed with noncalcified arterial segments on plain radiography and generally are found near arterial branch points in medium-sized conduit arteries. In contrast, medial arterial calcification (MAC) involves deeper layers of the arterial wall; tends to affect the artery diffusely, appearing as a linear contiguous tram-track pattern of calcification on plain radiography; and often involves smaller muscular arteries such as the radial artery, intermammary arteries, and arteries in the ankle and foot. Both are related to CVD events, but potentially through different mechanisms. Atherosclerotic calcification may be marking the total burden of atherosclerosis, whereas MAC may lead to arterial stiffness and left ventricular hypertrophy. Existing data suggest that altered mineral metabolism may promote MAC, whereas heightened inflammation and oxidative stress contribute to atherosclerosis. Dysregulation of normal anticalcification factors and elastin degradation are common to both processes. Risk of vascular calcification also may be increased by the use of certain medications in the setting of chronic kidney disease. This review compares and contrasts known risk factors for MAC and atherosclerosis, describes existing and emerging technologies to distinguish between them, and reviews the existing literature linking each with CVD events in dialysis patients and in other settings.