Epstein-Barr virus (EBV) is one of the most common and successful human viruses, infecting more than 90% of the world’s adult population. Despite its strong tumorigenic potential, most virus carriers remain healthy due to maintenance of a delicate balance between the host’s immune system, which limits production of virus particles, and the virus, which persists for the duration of the host’s life. New data show that this balance is altered on a subtle level in patients with multiple sclerosis (MS) and other autoimmune diseases who show enhanced as well as less restricted T-cell and antibody responses to EBV-encoded antigens. Such quantitatively and qualitatively distinct immune responses and the virus’ unique ability to immortalize B cells as well as to continuously stimulate strong T-cell responses during persistent infection suggest a possible role for EBV in the initiation and progression of symptomatic autoimmunity. We hypothesize that EBV promotes both autoimmune B and T-cell responses. EBV gene products might stimulate cross-reactive autoimmune B cells directly or increase their survival after infection. In addition, autoimmune T cells could be maintained via molecular mimicry between autoantigens and EBV antigens, and via the Th1 polarizing cytokine milieu of protective antiviral T-cell immunity. A better understanding of how EBV and EBV-specific immune control mechanisms interfere with the evolution of autoimmunity may generate a rationale for novel EBV-targeting therapeutic strategies aimed at the prevention and more efficient treatment of autoimmune diseases.