Abstract: Despite the big progresses in the field of regenerative medicine, the loss of neurons remains essentially an unresolved challenge. Among the different approaches under investigation, there are great expectations on stem and progenitor cells-based strategies. Due to their capacity to home to the site of injury and theoretically generate all kinds of neuronal cells, stem cells seem the ideal candidates for targeted therapeutic interventions also in light of the lack of spontaneous regeneration of  the central nervous system. Unfortunately, the substantial failure to replace dead or dysfunctional cells has limited the development of stem cells-based therapies. This aspect is especially evident for the central nervous system due to the complex architecture of the tissue, the inherent fragility of mature neurons and the lack of methods to control and guide the proliferation and differentiation of neuronal precursors. However, there is compelling evidence that stem and progenitor cells are able to support different healing processes by means of paracrine actions. Taking advantage of these characteristics, researchers have investigated the cyto-protective and restorative activities of the factors released by in vitro cultured stem cells in the form of conditioned medium (CM).