Although viruses are commonly cited as triggers for autoimmune disease, the actual mechanisms by which they initiate autoimmunity are unknown. Molecular mimicry is the most popular hypothesis, and it proposes that viral antigens that share homologies with host antigens generate an immune response that damages host tissue. The viral antigen may not be needed for perpetuation of the disease, and cross-reacting immune responses can involve humoral, cellular, or both types of reactivity. Linear and conformational epitopes may be involved, and foreign antigens do not need to share exact amino acid sequences with self-proteins to activate autoreactive T cells. Bystander effects can enhance the autoimmune process if previously sequestered or cryptic antigens are exposed to the immune system, and superantigens that are produced by the pathogen and are not MHC restricted can result in marked polyclonal activation of CD4 and CD8 T cells. Future studies must differentiate the targets of pathologic immunity and distinguish self-antigens from infectious nonself-antigens. Transgenic animal models of AIH are needed to assess the pathogenicity of the antigenic targets.