Abstract: MS is a neurodegenerative disease affecting around 2.5 million people worldwide, representing the second cause of disabilities in the young adult population. MS is a demyelinating pathology which originates in the autoimmune attack of T and B lymphocytes against myelin. This lack of myelin leads, in turn, to axonal degeneration, neuronal death and the consequent neurological disabilities (Franklin and Ffrench-Constant, 2017). A main hallmark of MS is a preserved local neuroinflammatory environment. It is now acknowledged that this persistent inflammatory scenario is a central and common condition in almost all neurodegenerative pathologies (as in Parkinson’s and Alzheimer’s diseases, among others) controlling and modulating the regulatory responses of the system to the triggering insult. In the case of MS, this original insult corresponds to the loss of myelin (Chitnis and Weiner, 2017; Franklin and Ffrench-Constant, 2017). Of particular interest for the understanding of MS progression, is how and when surrounded pro- and anti-inflammatory cytokines and chemokines modulate cross-glial communication in demyelinated lesions. After a demyelinated insult there is an -unfortunately deficient or incomplete- spontaneous myelin repair process (i.e., remyelination), characterized by the highly interdependent function of microglia, astrocytes and oligodendroglia, the latest corresponding to cells responsible for the formation of myelin in the central nervous system (CNS) (Chitnis and Weiner, 2017; Franklin and Ffrench-Constant, 2017). For instance, it is known that signaling molecules released by microglia induce the activation of astrocytes and promote differentiation of oligodendrocytes in demyelinated areas (Franklin and Ffrench-Constant, 2017). Similarly, astrocyte activity and secretion can promote oligodendrocyte maturation (Franklin and Ffrench-Constant, 2017). In the complex cellular interaction observed in demyelinated lesions, connexin (Cx)-based channels and hemichannels has been pointed out as a major components underlying glial communication (Vejar et al., 2018). However, less attention has been paid to the putative role of pannexin (Panx)- based channels, a functional equivalent of Cxs, usually involved in inflammatory processes, particularly in the CNS. Here we discuss evidence supporting a role of pannexin-based channels on the progression of MS that, we believe, deserves further investigation.