gammadelta T cells represent a small subpopulation of T cells expressing a restricted repertoire of T-cell receptors and, unlike alphabeta T cells, function more as cells of the innate immune system. These cells are found in skin and mucosal sites as well as secondary lymphoid tissues and frequently act as first line of defense sentinels. gammadelta T cells have been implicated in the pathogenesis of demyelinating disease, although little was known regarding their trafficking and effector functions. In this Mini-Review, we highlight recent studies demonstrating that gammadelta T cells migrate rapidly to the CNS during experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. gammadelta T-cell trafficking to the CNS is independent of beta(2)-integrins and occurs well before onset of clinical signs of disease, peaking early during the acute phase of disease. gammadelta T-cell-mediated production of inflammatory cytokines, including interferon-gamma and tumor necrosis factor-alpha, appears critical for EAE development, suggesting that these cells may set the stage for activation of other subsets of infiltrating effector cells. These data suggest that gammadelta T cells or subsets of gammadelta T cells may represent a new therapeutic target in demeylinating disease.