The aim of this paper is to review the present knowledge about Endocan expression, structure, and activity, with a special focus on the recent developments that have been highlighting that Endocan, as an endothelial proteoglycan not only is a biomarker of neoangiogenesis but also appears today as a signature of the tumor progression when it is expressed by the tumor cells themselves. This evidence concerns the gene ESM1 and neoplasm.