• The review focuses on the role of EphBs and ephrin-Bs at the synapse: during development, in the mature brain and in disease. Key findings include: • EphBs are essential for excitatory synapse formation and regulate the NMDAR at the mature synapse. • Ephrin-Bs mediate EphB signaling and recruit and retain key synaptic scaffolding proteins such as PSD-95 at the synapse. • EphBs and ephrin-Bs are linked to a number of neurological disorders, particularly those linked to NMDAR dysfunction like Alzheimer's, NMDAR-encephalitis, and pain. • EphBs and ephrin-Bs are required during each phase of the life of the glutamatergic spine synapses. Synapse formation between neurons is critical for proper circuit and brain function. Prior to activity-dependent refinement of connections between neurons, activity-independent cues regulate the contact and recognition of potential synaptic partners. Formation of a synapse results in molecular recognition events that initiate the process of synaptogenesis. Synaptogenesis requires contact between axon and dendrite, selection of correct and rejection of incorrect partners, and recruitment of appropriate pre- and postsynaptic proteins needed for the establishment of functional synaptic contact. Key regulators of these events are families of transsynaptic proteins, where one protein is found on the presynaptic neuron and the other is found on the postsynaptic neuron. Of these families, the EphBs and ephrin-Bs are required during each phase of synaptic development from target selection, recruitment of synaptic proteins, and formation of spines to regulation of synaptic plasticity at glutamatergic spine synapses in the mature brain. These roles also place EphBs and ephrin-Bs as important regulators of human neurological diseases. This review will focus on the role of EphBs and ephrin-Bs at synapses. [ABSTRACT FROM AUTHOR]