Membrane associated guanylate kinase proteins (MAGUKs) play a key role in the regulation of the intracellular trafficking and synaptic localization of ionotropic glutamate receptors. In particular, the postsynaptic density-95-like subfamily of MAGUKs (PSD-MAGUKs) organizes ionotropic glutamate receptors and their associated signaling proteins in the postsynaptic density of the excitatory synapse regulating the strength of synaptic activity. Several recent observations clearly put forward the idea that alterations of PSD-MAGUK protein function such as alterations of PSD-MAGUK protein interaction with N-methyl-D-aspartate (NMDA) receptors regulatory subunits are common events in several CNS disorders. With this view, a better knowledge and understanding of PSD-MAGUK function as well as of the molecular events regulating PSD-MAGUK-mediated interactions in the glutamatergic synapse could lead to the identification of new pharmaceutical targets for the therapy of CNS disorders.