The vascular extracellular matrix is responsible for the mechanical properties of the vessel wall and is also involved in biologic processes such as cellular adhesion, regulation, and proliferation. Thus, an adequate balance of its components is necessary for the normal functioning of the vasculature. Vascular disorders affect this balance, and this plays a key role in their pathophysiology. Atherogenesis is accompanied by an increase in matrix deposition in response to low-density lipoprotein accumulation. However, this matrix, mainly collagen, also has a protective role by forming a fibrous cap around the lipid core, avoiding contact with blood. A decrease in the amount of collagen will weaken the cap and make it prone to rupture, leading to thrombosis and acute coronary syndromes. In hypertension, the increase in matrix deposition results in vascular stiffness and cardiac dysfunction. In this paper, we discuss the relevance of matrix regulation in these conditions.