The technology of cloning viral genes and expressing them in vivo under cell-specific promoters allows to dissect the role of viruses, host self proteins, host genetics and immune responses in the complex etiology of autoimmune disease. Expression of a viral transgene, that is really a marker for a host “self” protein per se in ß cells of the islets of Langerhans, need not cause disease. In our model, expression of a viral gene was not associated with disease over the lifetime of the animal. However, when the host becomes infected with a virus encoding the same gene as the transgene or one closely related to it, a resultant immune response directed against the virus also recognizes the transgene leading to progressive T-cell-mediated response and destruction of the tissue expressing the viral (“self”) gene, leading to autoimmune disease. This multifactorial process is influenced by whether the viral transgene is expressed in the thymus as well as in the disease-related cell or target tissue. Thymic expression influences negative selection of responder lymphocytes and thus delays the onset of the autoimmune disorder. Further, the MHC haplotype or other background genes of an individual undergoing autoimmune dysfunction play a role in the affinity of binding of the transgene products to the MHC molecule and influence the degree of negative selection that occurs, thereby influencing the vigor of the resulting immune response. The current ability to express host or viral genes in unique cell populations, and to make double- or triple-tg mice in which various cytokine genes or lymphocyte activation genes can be expressed along with the viral gene, offers a unique possibility for molecular dissection of autoimmunity. With the information on hand, approaches to the prevention and treatment of human autoimmune disease are likely to be uncovered. Finally, animal models are available in which the onset, progression and control of molecular mimicry can be evaluated. Future studies should define roles played by cytokines, bystander and immune-specific cross-reactivity to viruses and other microbes in several autoimmune diseases.