Eph receptors and their ephrin ligands were identified in the late 1980's. Subsequently, they were linked to different physiological and pathophysiological processes like embryonic development, angiogenesis, and tumorigenesis. In this regard, recent work focused on the distribution and effects of Eph receptors and ephrins on tumor cells and tumor microenvironment. The purpose of this review is to outline the role of these molecules in physiological angiogenesis and pathophysiological tumor angiogenesis. Furthermore, novel therapeutical approaches are discussed as Eph receptors and ephrins represent attractive targets for antiangiogenic therapy.