Self-repair of the adult brain is limited – most diseases lack effective therapy. In order to better understand how a regenerative response can be achieved, studying mechanisms shaping the neurogenic niche, from environmental factors to intrinsic signaling, is of significance. My work highlights the enormous plasticity of the CNS and the crucial role of serotonin in affecting the behavior of neural stem/progenitor cells. It allows important insights into antidepressant strategies that involve physical activity, adult neurogenesis, BDNF, and signals of the vascular niche. Future research will have to elucidate the systemic cues and targets that regulate neuroplasticity and how they become deregulated in disease. It remains to be seen how they will contribute to the development of novel therapies and biomarkers for cognitive disorders.