Myocardial infarction can lead to irreversible heart failure. In an attempt to restore function in the failing heart, tissue-engineered cardiac constructs can be applied to repopulate scar tissue with a new pool of contractile cells. Effective engineering of viable thick complex tissue-constructs requires intense vascularization. Furthermore, endothelial-cardiomyocyte crosstalk plays a key role in mutually enhancing tissue functionality, which can further improve construct survival. The ability to generate an engineered, vascularized muscle tissue was demonstrated by us using the skeletal and the cardiac muscle models. In the skeletal model, we showed that prevascularization of the construct promoted perfusion of the graft. More recently, we successfully generated a beating human cardiac muscle-construct, containing an endothelial network, by co-culturing human embryonic stem cell-derived-cardiomyocytes, fibroblasts, and endothelial cells within biodegradable scaffolds. Such muscle-constructs could contribute significantly to the emerging discipline of cardiovascular regenerative medicine as well as to the study of the important role of tissue vascularization.