The origin of the epicardium and the formation of the early blood vessels of the heart prior to the opening of the coronary arteries from the aorta have been studied in the 9-13.5 day post coitum (dpc) mouse embryo heart. The epicardium begins to appear by 9 dpc. The majority of the epicardial cells derive from the somatopleural investment of the septum transversum, from where they migrate, associated to form vesicles, to the dorsal aspect of the ventricles and atria. The epicardial cells then migrate over the lateral surfaces and the AV sulcus to the ventral aspect of the heart. In the subepicardial space around the sulci, the proliferating epithelial tissue is found, also in vesicular form, for a time. The ventrally migrating primordial epicardial tissue ensheaths lastly the truncus arteriosus, while the sinus venosus is coated with epicardium ab initio, where (and also in the SA sulcus) the epicardial cells derive in part from the cuboidal cells of the pleuroperitoneal canal and in part from the somatopleural cells. The early blood vessel formation follows in space and time the development of the epicardium. The first blood vessels appear by dpc by the invagination of the endocardium into the early sinus muscle, and at the same time in the ventricular chamber by the encasing of the endocardium, as the trabeculae become consolidated into the myocardial walls. By this process sinusoids are formed, some of which penetrate through the myocardium and which, by rapid proliferation, form an interconnected subepicardial plexus. These capillaries proliferate ventrally in the wide subepicardial space, reaching the septating truncus, in which the aorta and pulmonary artery are developing. The definitive coronary artery openings appear by 13 dpc, allowing the high pressure blood from the aorta to flow into a preexisting vascular bed.