Communication between endothelial cells and cardiomyocytes regulates not only early cardiac development but also adult cardiomyocyte function, including the contractile state. In the normal mammalian myocardium, each cardiomyocyte is surrounded by an intricate network of capillaries and is next to endothelial cells. Cardiomyocytes depend on endothelial cells not only for oxygenated blood supply but also for local protective signals that promote cardiomyocyte organization and survival. While endothelial cells direct cardiomyocytes, cardiomyocytes reciprocally secrete factors that impact endothelial cell function. Understanding how endothelial cells communicate with cardiomyocytes will be critical for cardiac regeneration, in which the ultimate goal is not simply to improve systolic function transiently but to establish new myocardium that is both structurally and functionally normal in the long term.