The extracellular matrix (ECM) forms the structural basis for the functional properties of different organs and tissues including the vasculature. Consequently, any alteration in the ECM may significantly influence the function of organs and tissues in question. This is also true for the cardiovascular system and its pathologies. Thus, therapies specifically targeting the ECM are likely very potent in the treatment of various diseases. Unfortunately, so far there are no therapies in clinical use primarily targeting the ECM. Nevertheless, most cardiovascular drugs are known to modulate the ECM and its macromolecules. However, their effects on the cardiovascular ECM are neither potent nor specific enough. Therefore, novel ECM targeting pharmacotherapies are desired. Here, the ECM of the cardiovascular tissue in health and disease as well as the effect of current cardiovascular drugs on the ECM are discussed in more detail. Furthermore, potential future pharmacotherapies targeting the ECM of the vasculature in various pathologies are presented.