Epstein-Barr virus (EBV) is a ubiquitous herpesvirus infecting more than 90% of adult population in the world. EBV is involved in the pathogenesis of a wide variety of malignancies, including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and lymphoproliferative disease of immunocompromised hosts. In addition, abundant evidence has been obtained implicating the virus in autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. In particular, seroepidemiological data strongly suggest that EBV is a prerequisite factor for the development of multiple sclerosis. Although no decisive theory has explained the mechanism of EBV's involvements in the pathogenesis of autoimmune diseases, a number of hypotheses have been presented, including molecular mimicry, bystander damage, mistaken self, and EBV infection of autoreactive B cells. In this review, evidence so far obtained to suggest a crucial role for EBV in triggering autoimmune diseases is summarized and hypothetical mechanisms of EBV's involvement in these diseases are discussed. In addition, results obtained from a recent humanized mouse model of EBV infection that reproduced rheumatoid arthritis-like erosive arthritis are described.