The postsynaptic density (PSD) is an ultrastructural specialization of the glutamatergic excitatory synapses, at the cytosolic surface of the postsynaptic membrane of dendritic spines. The PSD is a highly organized transductional machinery that tunes the excitatory signaling from presynaptic terminals. Hundreds of proteins have been isolated in the PSD including glutamate receptors, kinases, as well as scaffolding, association, and cytoskeleton proteins. Homer is a family of PSD proteins involved in the cross-interaction between metabotropic glutamate receptors and intracellular signal transduction systems. Homer1a (H1a) is the only inducible isoform of the Homer family, whereas all the other isoforms (H1b/c, H2, and H3) are constitutively expressed. Further, H1a exhibits a ligand-binding motif but not the homomultimerization domain. H1a induction disrupts the clusters of PSD factors formed by constitutive Homers. Several stimuli have been demonstrated to induce H1a gene expression in the central nervous system, including the administration of antipsychotics. Homer-regulated PSD remodeling may represent a mechanism of synaptic plasticity and a putative target for both pharmacotherapy and pharmacogenomics of behavioral disorders.