Ephrin ligands and their cognate Eph receptors guide axons during neural development and regulate synapse formation and neuronal plasticity in the adult. Because ephrins are tethered to the plasma membrane and possess reverse signaling properties, the Eph-ephrin system can function in a bidirectional, contact-mediated fashion between two opposing cells. Eph receptors expressed on dendrites are activated by ephrins (on axons or on astrocytes) and regulate spine and synapse formation. They also participate in activity-induced long-term changes in synaptic strength such as long-term potentiation (LTP). When expressed on axon terminals, ephrins promote presynaptic differentiation and enhance neurotransmitter release, thereby supporting presynaptic forms of LTP. In some cases, Eph receptors can simply act as ligands for ephrins without any requirement for Eph receptor signaling, suggesting that the system does not always function bidirectionally.