The concept of repair of the nervous system by adult stem cells has recently evolved from the original hypothesis that tissue regeneration could have been achieved through stem cell differentiation into neural cells to the current vision that they act mainly by means of paracrine mechanisms. In a recent paper from Voulgari-Kokota and colleagues in the July issue of Experimental Neurology it was shown that bone marrow-derived mesenchymal stem cells (MSC) can protect against glutamate excitotoxicity in a mouse model of temporal lobe epilepsy and that conditioned medium from MSC could rescue primary cortical neurons from glutamate-receptor induced cell death. Other studies have emphasized that MSC secretome may suffice to recapitulate many of the effects carried out by these cells on immune and tissue resident cells. However, MSC priming by local cues, upon interaction with the host environment, represents a prerequisite to maximally enhance their therapeutic plasticity. Future studies will have to resolve if stem cell transplantation is still preferable over the administration of their secreted factors.