This chapter describes a short historical overview of the progress in endothelium research and point the importance of organ-selective characteristics according to the present knowledge about endothelium biology. Uncovering the advantages that the endothelial cell properties and characteristics provide for the development of future targeted therapies, the review describes why mature endothelial cells due to their organ-specificity can be useful to target diseased organs. In the same line, endothelium properties will be exploited to make the endothelial cells a disease marker, e.g., in diabetes, stroke, cancer, inflammation, or ischemia and to provide a potential diagnostic indicator for the estimation of metastatic progression. New perspectives are thus opened by endothelial cells that can be considered both as a reporter and a target. These features can be combined with new cell-mediated and cell-targeted therapeutics designed to correct angiogenesis. Examples of such possible applications are detailed in the repair of tumor angiogenesis with help of endothelial cell precursors through their ability to target the pathologic angiogenesis and participate to normalization of the pathologic vasculature. The hypothesis that normalized angiogenesis may provide an efficient treatment, working as adjuvant to classical therapies, is being developed. The objective is to reach a mechanical stabilization that should result in an advantageous change of the tumor microenvironment.