Reports showing that W/W(v) mice are protected from experimental autoimmune encephalomyelitis (EAE, a murine model of multiple sclerosis), have implicated mast cells as an essential component in disease susceptibility, but the role of mast cell trafficking has not been addressed. In this study, we have used both mast cell transplantation and genetic mutations (Cd34(-/-), W/W(v), W(sh)/W(sh)) to investigate the role of mast cell trafficking in EAE in detail. We show, for the first time, that bone marrow-derived mast cells are actively recruited to the CNS during EAE. Unexpectedly, however, we found that EAE develops unabated in two independent genetic backgrounds in the complete absence of mast cells or bone marrow-derived mast cell reconstitution. We conclude that although mast cells do accumulate in the brain and CNS during demyelinating disease via peripheral mast cell trafficking, they are completely dispensable for development of disease.