Eph receptor tyrosine kinases and their Ephrin ligands represent an important signaling system with widespread roles in cell physiology and disease. Receptors and ligands in this family are anchored to the cell surface; thus Eph/Ephrin interactions mainly occur at sites of cell-to-cell contact. EphB4 and EphrinB2 are the Eph/Ephrin molecules that play essential roles in vascular development and postnatal angiogenesis. Analysis of expression patterns and function has linked EphB4/EphrinB2 to endothelial cell growth, survival, migration, assembly, and angiogenesis. Signaling from these molecules is complex, with the potential for being bidirectional, emanating both from the Eph receptors (forward signaling) and from the Ephrin ligands (reverse signaling). In this review, we describe recent advances on the roles of EphB/EphrinB protein family in endothelial cell function and outline potential approaches to inhibit pathological angiogenesis based on this understanding.