Calcification of extracellular matrix (ECM) can be either physiological or pathological. Physiological calcification (or mineralization) of ECM is restricted to bones, teeth and, to a lesser extent, growth plate cartilages. Pathological calcification appears often in the ECM of arteries where it is a frequent complication of atherosclerosis. However, calcification of the ECM of arteries is not restricted to atherosclerosis. Indeed, human diseases have been described that are characterized by calcification of the aortic media in the absence of any atherosclerotic lesions. The existence of these rare diseases, along with several mouse models recently generated and discussed below, indicates that the formation of atherosclerotic lesions and the calcification of the artery ECM are controlled by different genetic pathways. This emerging knowledge has implications for our understanding of ECM calcification beyond atherosclerosis.