The gap junctions (GJs), which form intercellular communicating channels between two apposing cells or form hemichannel with extracellular environment, perform crucial functions to maintain small molecule homeostasis. The central nervous system (CNS) GJs are important for maintenance of myelin sheath and neuronal activity. Connexin (Cx) proteins are building blocks of GJs. Recent cell-biological investigations show that amongst the CNS specific Cxs, the most abundant Cx protein, Cx43 and its oligodendrocytic coupling partner Cx47 primarily important for maintenance of CNS myelin. Recent investigations elucidate that the expression of Cx43 and Cx47 is very important to maintain K? buffering and nutrient homeostasis in oligodendrocytes, CNS myelin and oligodendrocyte function. The investigations on Multiple Sclerosis (MS) patient samples and EAE hypothesized that the functional loss of Cx43/Cx47 could be associated with spread of chronic MS lesions. Exploring the mechanism of initial GJ alteration and its effect on demyelination in this model of MS might play a primary role to understand the basis of altered CNS homeostasis, observed during MS. In this review, we mainly discuss the role of CNS GJs, specifically the Cx43/Cx47 axis in the perspective of demyelination.