Growing evidence suggests that mast cells (MCs) play a crucial role in the inflammatory process and the subsequent demyelination observed in patients suffering from multiple sclerosis (MS). Although no consensus exists on the role of mast cells in multiple sclerosis, recent results from animal models clearly indicate that these cells act at multiple levels to influence both the induction and the severity of disease. In addition to changing our views on the pathophysiology of multiple sclerosis, the concept that mast cells are critical for the outcome of the disease could have an important impact on the development of new therapeutic approaches.