Abstract: Mesenchymal stem cells (MSCs) are multipotent adult stem cells of mesodermal origin that can be isolated from various tissues, including bone marrow, tooth pulp, adipose tissue, and umbilical cord. MSCs have gained significant attention in regenerative medicine due to their ability to modulate the immune system and favor tissue repair. MSCs enrich the medium in which they are cultivated with a broad range of bioactive molecules, including growth factors, cytokines, chemokines, enzymes, nucleic acids, and extracellular vesicles that collectively compose the MSC secretome. An increasing number of pre-clinical studies suggest that delivering in vivo an MSC-conditioned medium (i.e., the medium collected from MSC cultures after at least 3 days of exposure) exerts neuroprotective and anti-inflammatory effects in a variety of neurological conditions, including chronic pain. Importantly, since therapies based on MSC transplantation are highly impaired by the limited cell survival in the host and by the potential occurrence of immunological adverse responses, MSC secretome represents a safer and more viable alternative to these therapies.