The incidence of autoimmune disorders is increasing worldwide. Several theories have been proposed to explain how the breakdown in the balance between autoregulatory immune pathways and pathogenic autoreactivity generates autoimmunity. On the basis of a large body of epidemiological, clinical and experimental evidence, it has been suggested that an unfortunate interplay of genetic susceptibility and environmental factors must play an important role in generating the abnormal autoimmune response. Although genetic factors have been well dissected, the environmental agents that may be causative of disease are still under investigation. Their discovery is obviously relevant because they enable us to devise preventive and therapeutic strategies in trying to halt the progress and ultimately treat this category of disorders. Among the environmental factors, infectious agents have been proposed as the best candidate triggers in the autoimmune pathogenesis. The observation that a long preclinical period often precedes the clinical onset of disease, in analogy to the clinical symptoms of AIDS, led to propose exogenous and endogenous retroviruses as suspected culprits for organ and non-organ specific autoimmune disorders. The hypothesis is revisited in this article in the light of our research experience over the past years and of relevant literature emerging in the field.