Epstein-Barr virus (EBV) has been associated with autoimmune diseases for over 40 years. However, the mechanisms by which EBV might promote autoimmune development remain elusive. Many of the hypotheses for the means by which EBV might achieve this incorporate the idea that autoimmune responses are initially immune responses against EBV proteins that crossreact with endogenous human proteins. However, recent evidence using transgenic mouse models suggests that B cells expressing the EBV-encoded protein latent membrane protein 2A (LMP2A) bypasses normal tolerance checkpoints and enhances the development of autoimmune diseases. Evidence from transgenic mouse models supports a paradigm in which LMP2A could promote autoimmune development. This novel model provides a framework to test potential mechanisms by which EBV could promote the development of autoimmune responses and might enable the identification of strategies to treat EBV-associated autoimmune diseases.