The receptor tyrosine kinase Eph and its membrane-bound ligand ephrin are emerging key players in synapse formation and plasticity in the central nervous system. Understanding how ephrin/Eph regulate synapse formation and functions is often complicated by the fact that both ligands and receptors are expressed in the pre-synaptic and post-synaptic neurons and upon their interaction, bi-directional signaling cascades can be triggered. By elucidating the respective downstream targets and generating signaling-deficient mutants, the specific roles of forward (Eph receptor) and reverse (ephrin) signaling are beginning to be unraveled. In this review, we summarize recent advances in our understanding of how ephrin and Eph differentially participate in specific aspects of synapse formation in developing neurons, and activity-dependent plasticity in the adult brain.