This chapter focuses on the interactions of vascular cells with the extracellular matrix (ECM) in atherosclerosis: (i) how these ECM proteins are regulated and (ii) how ECM proteins play their roles in atherosclerosis, regulating low-density lipoprotein (LDL) metabolism, participating in the infiltration and differentiation of smooth muscle cells (SMCs) and macrophages, controlling matrix remodeling through feedback signaling to proteinases, and influencing the development of plaque rupture. The composition of ECM shows changes after arterial injury and during atherosclerotic plaque development. SMC proliferation is an important event for the growth of atherosclerotic plaque, with collagen Iα critical regulator of proliferation. Atherosclerotic plaques are covered by a cap rich in fibrillar collagens and elastin. The cap confers considerable stability to the plaque, protecting against rupture and the devastating complication of thrombosis. In addition to their biological activities, the ECM is indeed a critical structural component of both the healthy and diseased vessel. © 2015 John Wiley & Sons, Inc.