In relation to ancient infections, a substantial number of retroviral sequences with persistent immunogenic potential were integrated within the human genome (HERVs). Under physiological conditions, coding sequences from HERVs can participate in cell/tissue homeostasis and physiological functions in an epigenetically controlled manner. However, HERV expression is susceptible to contribute to various pathologies, including autoinflammatory and autoimmune disorders, when reprogrammed by exogenous stimuli such as drugs or microbial infections. Both innate and adaptive components of the immune system can be mobilized in response to deregulated/de-repressed expression of HERV determinants and thereby, modify immune tolerance to tissue antigens. Self-directed immune responses induced/worsened by HERV expression are suspected to participate in both tissue-specific and systemic disorders. A substantial level of mechanistic investigation is needed to better delineate the impact of HERV expression in diseases in general, and in inflammation and autoimmunity in particular.