Cell communication is needed for organ function and stress responses, especially in the heart. Cardiac fibroblasts, cardiomyocytes, immune cells, and endothelial cells comprise the major cell types in ventricular myocardium that together coordinate all functional processes. Critical to this cellular network is the non-cellular extracellular matrix (ECM) that provides structure and harbors growth factors and other signaling proteins that affect cell behavior. The ECM is not only produced and modified by cells within the myocardium, largely cardiac fibroblasts, it also acts as an avenue for communication among all myocardial cells. In this Review, we discuss how the development of therapeutics to combat cardiac diseases, specifically fibrosis, relies on a deeper understanding of how the cardiac ECM is intertwined with signaling processes that underlie cellular activation and behavior.