Innate immune sensors of foreign nucleic acids are essential for antiviral immunity, but these same sensors can cause autoimmune disease through inappropriate detection of self-nucleic acids. The sources of the endogenous RNA and DNA that trigger autoreactive responses include chromatin and ribonucleoproteins that are the targets of autoantibodies in numerous autoimmune diseases, including systemic lupus erythematosus. In this review, I discuss recent data implicating endogenous retroelements-viruses that make up a substantial fraction of our genomes-as an important source of endogenous nucleic acids that can cause autoimmune disease. Understanding this potentially pathologic role for retroelements and the precise mechanisms by which their genomes are sensed and metabolized has important implications for the diagnosis and treatment of numerous autoimmune disorders.