Extracellular matrix proteins are regulated by metzincin proteases, like the disintegrin metalloproteinases with thrombospondin motifs (ADAMTS) family members. This review focuses on the emerging role which ADAMTS-4 might play in vascular pathology, which has implications for atherosclerosis and vessel wall abnormalities, as well as for the resulting diseases, such as cardiovascular and cerebrovascular disease, aortic aneurysms, and dissections. Major substrates of ADAMTS-4 are proteoglycans expressed physiologically in smooth muscle cells of blood vessels. Good examples are versican and aggrecan, principal vessel wall proteoglycans that are targeted by ADAMTS-4, driving blood vessel atrophy, which is why this metzincin protease was implicated in the pathophysiology of vascular diseases with an atherosclerotic background. Despite emerging evidence, it is important not to exaggerate the role of ADAMTS-4 as it is likely only a small piece of the complex atherosclerosis puzzle and one that could be functionally redundant due to its high structural similarity to other ADAMTS family members. The therapeutic potential of inhibiting ADAMTS-4 to halt the progression of vascular disease after initialization of treatment is unlikely. However, it is not excluded that it might find a purpose as a biomarker of vascular disease, possibly as an indicator in a larger cytokine panel.