Anti-angiogenic therapy is currently a commonly accepted and rapidly developing approach in oncology and other pathologies linked to aberrant neovascularization. Discovery and validation of additional molecular targets in angiogenesis is needed due to the limitations of the existing clinical therapeutics inhibiting activity of vascular endothelial growth factor (VEGF) and its receptors. A brief review of normal and pathological biological functions of the Eph family of receptor tyrosine kinases and their ephrin ligands is presented, and the approaches to developing therapeutics with anti- and pro-angiogenic and anti-tumor activity based on selective molecular modulation of Eph-ephrin signaling pairs are discussed. Functional roles of Eph-kinases and ephrins in such mechanisms of cancerogenesis as cell proliferation and invasion are also addressed.