Excitatory synapses are characterized by an electron-dense thickening at the cytoplasmic surface of the postsynaptic membrane, called the postsynaptic density (PSD). The PSD is a fibrous specialization of the submembrane cytoskeleton approximately 30-40 nm thick and about 100 nm wide. Hundreds of molecules have been identified in the PSD: ion-gated and G-protein-coupled receptors, association, adaptors, and scaffolding proteins, key enzymes involved in phosphorylation-dephosphorylation mechanisms, and cytoskeletal proteins. Each of these proteins may have a pivotal function in setting the molecular scenario for the development of synaptic plasticity. Scaffolding proteins are major players in the organization of the postsynaptic signal transduction machinery,they regulate receptor trafficking and clustering, modulate axon pathfinding,and drive the correct targeting of neuronal proteins to their appropriate cytoplasmic compartment. Emerging findings suggest a relevant involvement of PSD scaffolding/adaptor proteins in behavior modulation in animal models of synaptic plasticity disorders and pharmacological isomorphisms.