Rasmussen's encephalitis is a devastating disease characterized by refractory epilepsy and progressive atrophy of one cerebral hemisphere. The only treatment option able to prevent seizures is the surgical disconnection of the affected hemisphere. The etiology of the disease remains unknown, but several laboratory findings have recently indicated the involvement of the immune system. Whether these findings represent an initiating event or the consequence of a not yet identified trigger factor must be elucidated. Nevertheless, these observations suggest the use of different immunomodulatory approaches (including corticosteroids, plasmapheresis, intravenous immunoglobulins and immunosuppressive drugs) that proved to be of variable efficacy in some patients, confirming the potential role of the immune system, at least in the perpetuation of the disease.