The scope of this manuscript is to review the literature concerning the physio-pathological role of CCL5 in controlling glutamate transmission in the CNS of healthy mammals, as well as of individuals and animals suffering from demyelinating disease, in order to highlight the main role of CCL5 as a modulator of the neuroimmune cross-talk in the “quad partite” synapse in CNS (Figure 2). The gene discussed is CCL5; the disease is demyelinating disease.