The development of new therapies for psychiatric disorders is of utmost importance, given the enormous toll these disorders pose to society nowadays. This should be based on the identification of neural substrates and mechanisms that underlie disease etiopathophysiology. Adult neural stem cells (NSCs) have been emerging as a promising platform to counteract brain damage. In this perspective article, we put forth a detailed view of how NSCs operate in the adult brain and influence brain homeostasis, having profound implications at both behavioral and functional levels. We appraise evidence suggesting that adult NSCs play important roles in regulating several forms of brain plasticity, particularly emotional and cognitive flexibility, and that NSC dynamics are altered upon brain pathology. Furthermore, we discuss the potential therapeutic value of utilizing adult endogenous NSCs as vessels for regeneration, highlighting their importance as targets for the treatment of multiple mental illnesses, such as affective disorders, schizophrenia, and addiction. Finally, we speculate on strategies to surpass current challenges in neuropsychiatric disease modeling and brain repair.