Conceptually, the initiation of autoimmune disease can be described as a three-stage process involving both genetic and environmental influences. This process begins with the development of an autoimmune cellular repertoire, followed by activation of these autoreactive cells in response to a localized target and, finally, the immune system's failure to regulate these self-reactive constituents. Viruses have long been associated with inciting autoimmune disorders. Two mechanisms have been proposed to explain how a viral infection can overcome immunological tolerance to self-components and initiate an organ-specific autoreactive process; these mechanisms are molecular mimicry and bystander activation. Both pathways, as discussed here, could play pivotal roles in the development of autoimmunity without necessarily excluding each other. Transgene technology has allowed us and others to examine more closely the roles of these mechanisms in mice and to dissect the requirements for initiating disease. These results demonstrate that bystander activation is the most likely explanation for disease development. Additional evidence suggests a further role for viruses in the reactivation and chronicity of autoimmune diseases. In this scenario, a second invasion by a previously infecting virus may restimulate already existing autoreactive lymphocytes, and thereby contribute to the diversity of the immune response.