Targeting of tumor vasculature is a promising strategy for cancer treatment. Among endothelial cell markers, Endoglin, a cell membrane glycoprotein, is emerging as an attractive therapeutic target on angiogenetic blood vessels, and it currently represents a powerful marker to quantify tumor angiogenesis. In normal human tissues, Endoglin is weakly expressed on erytroid precursors, stromal cells and activated monocytes, whereas it is strongly expressed on proliferating endothelial cells. In human neoplasias of different histotype, Endoglin is mainly present on endothelial cells of both peri- and intra-tumoral blood vessels, while it is weakly expressed or absent on neoplastic cells. Endoglin is an accessory component of the receptor complex of Transforming Growth Factor (TGF)-beta, a pleiotropic cytokine that modulates angiogenesis by the regulation of different cellular functions including proliferation, differentiation and migration. Interestingly, the over-expression of Endoglin antagonizes several cellular responses to TGF-beta1, while its down-regulation potentiates cellular responses to TGF-beta1. In animal models, administration of radiolabeled anti-Endoglin monoclonal antibodies (mAb) efficiently images primary tumors, and naked or conjugated anti-Endoglin mAb suppress angiogenesis and tumor growth. In this review we will summarize the complex of experimental evidences pointing to Endoglin as a vascular target to design innovative bioimmunotherapeutic strategies in human neoplasias.