The Eph receptors are the largest sub-family of Receptor Tyrosine Kinases (RTK). They, together with their ephrin ligands, play central roles in cell-cell communication during development, and also in the maintenance of a normal adult physiology. Their malfunction, therefore, can contribute to various human diseases. Since the structures of the Eph receptors and ephrins are by now well characterized, there has been extensive recent work to develop ways to manipulate their action in order to achieve therapeutic benefits. Although few reagents have progressed to clinical trials thus far, it is evident that the Eph receptors are valid targets for therapeutic drugs. In this review we first summarize studies on the three-dimensional structures of Eph receptors. We then give an overview on small molecule inhibitors and activators using Ephs as targets. We put a special focus on the latest developments in the field of monoclonal antibodies and antibody fragments for inhibiting or activating the Eph/ephrin signaling.