Neuropsychiatric diseases are manifested by maladaptive behavioral plasticity. Despite the greater understanding of the neuroplasticity underlying behavioral adaptations, pinpointing precise cellular mediators has remained elusive. This has stymied the development of pharmacological interventions to combat these disorders both at the level of progression and relapse. With increased knowledge on the putative role of the transforming growth factor (TGF- β) family of proteins in mediating diverse neuroadaptations, the influence of TGF-β signaling in regulating maladaptive cellular and behavioral plasticity underlying neuropsychiatric disorders is being increasingly elucidated. The current review is focused on what is currently known about the TGF-β signaling in the central nervous system in mediating cellular and behavioral plasticity related to neuropsychiatric manifestations.