Virus infections have been implicated in the initiation of multiple human autoimmune diseases. This article focuses on reviewing the role of viruses in initiation, progression, and perpetuation of autoimmune diseases. Various mechanisms by which virus infections can induce autoimmune responses including molecular mimicry, epitope spreading, direct bystander activation, and release of cryptic epitopes are discussed. Evidence implicating virus infections in the pathogenesis of various human autoimmune diseases is reviewed. Last, the characteristics of animal models that have been developed for the study of the potential role of viruses in the initiation and progression of autoimmune disease are reviewed.