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The PE arises from the lateral plate mesoderm (LPM) and is present in all vertebrate species. During development, mesothelial cells of the PE reach the naked myocardium either as free\u2010floating aggregates in the form of vesicles or via a tissue bridge; subsequently, they attach to the myocardium and, finally, form the third layer of a mature heart\u2014the epicardium. After undergoing epithelial\u2010to\u2010mesenchymal transition (EMT) some of the epicardial cells migrate into the myocardial wall and differentiate into fibroblasts, smooth muscle cells, and possibly other cell types. Despite many recent findings, the molecular pathways that control not only proepicardial induction and differentiation but also epicardial formation and epicardial cell fate are poorly understood. Knowledge about these events is essential because molecular mechanisms that occur during embryonic development have been shown to be reactivated in pathological conditions, for example, after myocardial infarction, during hypertensive heart disease or other cardiovascular diseases. Therefore, in this review we intended to summarize the current knowledge about PE formation and structure, as well as proepicardial cell fate in animals commonly used as models for studies on heart development. 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