The Eph receptors and their ephrin ligands have developmental roles in axon guidance and blood vessel formation and continue to function in the adult nervous system and at sites of adult angiogenesis. In the adult brain, the Eph receptors regulate the structure and physiological function of excitatory synapses through multiple mechanisms. The EphA4 receptor is highly expressed in hippocampal pyramidal neurons and concentrated on dendritic spines, which are small knob-like protrusions on dendrites that receive the majority of excitatory synaptic input. The enlarged head and narrow neck of dendritic spines are believed to facilitate synaptic transmission by biochemically isolating the synapse, located on the spine head, from the dendritic shaft. Spines are dynamic structures and their morphological remodeling likely contributes to synaptic plasticity, which is essential for learning and storing long-term memories. We recently showed that the signaling activity of the EphA4 receptor-which can be stimulated by the ephrin-A3 ligand located on perisynaptic glial processes-causes the retraction of dendritic spines. In contrast, inhibiting EphA4 signaling causes spine elongation and disorganization. This evidence suggests that EphA4 and ephrin-A3 mediate a new form of neuron-glia communication, which regulates dendritic spine structural plasticity. We will discuss our work on EphA4 signaling pathways that affect dendritic spines.