Cardiovascular complications due to accelerated atherosclerosis and arterial stiffening are the leading cause of morbidity and mortality in the Western society. Both pathologies are frequently associated with vascular calcification. Deposits of calcium phosphate salts, mainly in form of hydroxyapatite, is the hallmark of vascular calcification. Calcification is frequently observed in atherosclerotic lesions (intimal calcification) associated with vascular smooth muscle cells (VSMCs) and macrophages. By contrast, medial calcification, occurring in the elastic region of the arteries, is almost exclusively associated with VSMCs, and is common in arteriosclerosis related to aging, diabetes, and chronic kidney disease. In extracellular fluids, a range of endogenous low- and high-molecular weight calcification inhibitors are present, including osteopontin, matrix-Gla proteins and Fetuin A. Moreover, pyrophosphate deficiency plays a key role in vascular calcification. Pyrophosphate is produced by extracellular hydrolysis of ATP and is degraded to phosphate by tissue non-specific alkaline phosphatase. Loss of function in the enzymes and transporters involved in the extracellular pyrophosphate metabolism leads to excessive deposition of calcium-phosphate salts. This review summarizes the current knowledge about endogenous mechanisms of protection against calcification in the aortic wall, focusing on the role of extracellular pyrophosphate metabolism in vascular smooth muscle cells and macrophages. Copyright © 2020 Elsevier B.V. All rights reserved.