Epstein-Barr Virus (EBV) is one of the most successful human viruses, infecting more than 90% of the adult population worldwide and persisting for the lifetime of the host. Individuals with a history of symptomatic primary EBV infection, called infectious mononucleosis, carry a moderately higher risk of developing multiple sclerosis (MS). In addition, EBV-specific immune responses, which crucially regulate the host-virus balance in healthy virus carriers, are altered in patients with MS. Although no data so far unequivocally support a direct etiologic role of the virus, recent studies allow for the development of testable hypotheses as to how EBV infection potentially promotes autoimmunity and central nervous system (CNS) tissue damage in MS.