After its initial formation the epicardium forms the outermost cell layer of the heart. As a result of an epithelial-to-mesenchymal transformation (EMT) individual cells delaminate from this primitive epicardial epithelium and migrate into the subepicardial space (Pérez-Pomares et al., Dev Dyn 1997; 210: 96–105; Histochem J 1998a; 30: 627–634). Several studies have demonstrated that these epicardially derived cells (EPDCs) subsequently invade myocardial and valvuloseptal tissues (Mikawa and Fischman, Proc Natl Acad Sci USA 1992; 89: 9504–9508; Mikawa and Gourdie, Dev Biol 1996; 174: 221–232; Dettman et al., Dev Biol 1998; 193: 169–181; Gittenberger de Groot et al., Circ Res 1998; 82: 1043–1052; Manner, Anat Rec 1999; 255: 212–226; Pérez-Pomares et al., Dev. Biol. 2002b; 247: 307–326). A subset of EPDCs continue to differentiate in a variety of different cell types (including coronary endothelium, coronary smooth muscle cells (CoSMCs), interstitial fibroblasts, and atrioventricular cushion mesenchymal cells), whereas other EPDCs remain in a more or less undifferentiated state. Based on its specific characteristics, we consider the EPDC as the ultimate ‘cardiac stem cell ‘. In this review we briefly summarize what is known about events that relate to EPDC development and differentiation while at the same time identifying some of the directions where EPDC-related research might lead us in the near future. Anat Rec Part A 276A: 43–57, 2004.© 2004 Wiley-Liss, Inc.