Epsins are a family of adaptor proteins involved in clathrin-dependent endocytosis. In the vasculature, epsins 1 and 2 are functionally redundant members of this family that are expressed in the endothelial cells of blood vessels and the lymphatic system throughout development and adulthood. These proteins contain a number of peptide motifs that allow them to interact with lipid moieties and a variety of proteins. These interactions facilitate the regulation of a wide range of cell signaling pathways. In this review, we focus on the involvement of epsins 1 and 2 in controlling vascular endothelial growth factor receptor signaling in angiogenesis and lymphangiogenesis. We also discuss the therapeutic implications of understanding the molecular mechanisms of epsin-mediated regulation in diseases such as atherosclerosis and diabetes.