Cardiologists have commonly conceived of the extra-cellular matrix as an inert collection of structural macromolecules that serve as a scaffold for cells. Rapidly accumulating evidence challenges this view. Matrix macromolecules can regulate key functions of cells, and the composition of the cardiovascular extracellular matrix is under strict control. These control mechanisms can act in a slow and almost imperceptible manner, causing long-term changes in tissue structure, but they can also be very rapid, facilitating almost immediate changes in cellular behavior. Here, we explore these new concepts in the context of certain common cardiovascular diseases.