<p>In the last two decades, stem cells (SCs) have attracted considerable interest for their research value and therapeutic potential in many fields, namely in neuroscience. On the other hand, the discovery of adult neurogenesis, the process by which new neurons are generated in the adult brain, challenged the traditional view that the brain is a static structure after development. The recent findings showing that adult neurogenesis has a significant role in brain plasticity, learning and memory, and emotional behavior, together with the fact that it is strongly dependent on several external and internal factors, have sparked more interest in this area. The mechanisms of adult neural stem cell (NSC) regulation, the physiological role of NSC-mediated neuroplasticity throughout life, and the most recent NSC-based therapeutic applications will be concisely reviewed. Noteworthy, due to their multipotency, self-renewal potential, and ability to secrete growth and immunomodulatory factors, NSCs have been mainly suggested for (1) transplantation, (2) neurotoxicology tests, and (3) drug screening approaches. The clinical trials of NSC-based therapy for different neurologic conditions are, nonetheless, mostly in the early phases and have not yet demonstrated conclusive efficacy or safety. Here, we provide an outlook of the major challenges and limitations, as well as some promising directions that could help to move toward stem cell widespread use in the treatment and prevention of several neurological disorders.</p> Graphical Abstract <p>Factors influencing neural stem cell plasticity and neurogenesis. Several intrinsic and extrinsic factors can modulate neural stem cells’ ability to change their fate and function and to generate new neurons in the brain. <i>CSF</i>, cerebrospinal fluid; <i>GCL</i>, granule cell layer; <i>SGZ</i>, subgranular zone. Created with BioRender.com</p> <p></p>