Viral infections in humans commonly result in the transient appearance of a variety of autoantibodies and, in some patients, the development of autoimmune tissue injury and disease. The capacity to cause or exacerbate an autoimmune process is common to many viruses, affecting mainly organs injured by the replicating virus, as demonstrated by several animal models. Viral "footprints" can often be found in patients with autoimmune diseases and include high titers of specific antiviral antibodies, identification of viral (retroviral) sequences, and the presence of alpha-interferons in the serum. Several mechanisms that are not mutually exclusive can account for the pathogenesis of virus-induced autoimmunity. Viruses may modify or release sequestered cellular proteins or affect the host's immune system by direct polyclonal activation of B cells, effects on immunoregulatory cells, and release of lymphokines. The appearance of antiviral antibodies may also be deleterious to the host through molecular mimicry, the generation of anti-idiotypic antibodies, or the formation of immune complexes. No single microorganism or mechanism can explain the extremely varied phenomena of autoimmunity, but growing evidence suggests that certain viral infections may lead to clinically manifest autoimmunity in individuals having genetic and possibly other predisposing factors.