The formation of the embryonic heart vasculature is a complex process and is the result of vasculogenic, angiogenic and arteriogenic mechanisms, involving cells from distinct origins. In the neonate and the adult, several sources of endothelial precursor cells (EPCs) have been identified that contribute to physiological and pathological vascularization, consistent with the concept of de novo vasculogenesis after birth, including in the heart. The existence of EPCs in the adult has offered the possibility to use these cells for revascularization of ischemic tissues. An important challenge for vascular regeneration in ischemic and post-infarction patients is now to identify the most adequate cell source and cell dose for sufficient revascularization. This review gives an overview of the cellular and molecular cues involved in the formation of the heart vasculature before and after birth and discusses some of the recent insights and outstanding questions on EPCs and other vascular progenitors-both from a biological and therapeutic perspective.