Multiple sclerosis (MS) is a neurological autoimmune disorder of the central nervous system (CNS), characterized by recurrent episodes of inflammatory demyelination and consequent axonal deterioration. The hallmark of the disease is the demyelinated plaque, a hypocellular area characterized by formation of astrocytic scars and infiltration of mononuclear cells. Recent studies have revealed that both innate and adaptive immune cells contribute to the pathogenesis of MS and its experimental autoimmune encephalomyelitis (EAE) model. Here, we review the current understanding of the role of mast cells in the pathogenesis of MS and EAE. Mast cells may act at the early stage that promote demyelination through interactions among mast cells, neurons, and other immune cells to mediate neuroinflammation. Studies from EAE model suggest that mast cells regulate adaptive autoimmune responses, present myelin antigens to T cells, disrupt the blood–brain barrier, and permit the entry of inflammatory cells and mediators into the CNS. Depletion or limiting mast cells could be a new promising therapeutic target for MS and EAE.