Multiple sclerosis is an autoimmune demyelinating disease of the central nervous system mainly mediated by Th1 and/or Th17 cells, which cross the blood-brain barrier. Recent evidence indicates that Th2 cells and mast cells, typically associated with allergic reactions, are also involved. Brain mast cells are critically located perivascularly and secrete numerous proinflammatory and vasoactive molecules that can disrupt the blood-brain barrier, a finding that precedes clinical or pathologic signs of multiple sclerosis. Brain mast cells in multiple sclerosis are activated by neural factors, including substance P, myelin basic protein, and corticotropin-releasing hormone, caused by acute stress, which induce release of several inflammatory mediators. Mast cells can stimulate activated T cells coming in contact with them at the blood-brain barrier, as well as after stimulation with myelin basic protein or substance P. Pretreatment with the flavone luteolin blocks mast cell stimulation and T cell activation, as well as experimental autoimmune encephalitis. Interactions between mast cells and T cells could constitute a new and unique therapeutic target for multiple sclerosis.