Although the etiology of systemic lupus erythematosus (SLE) remains unclear, there is substantial circumstantial evidence that the development of SLE is dependent on environmental, genetic, and retroviral factors. SLE patients produce high titer antibodies to various retroviral proteins, including Gag, Env, and Nef of HIV and HTLV, in the absence of overt retroviral infection. We review the factors linking HERVs to SLE and consider the various processes utilized by endogenous retroviruses in the etiopathogenesis of SLE. In particular, we consider the role of HTLV-1-related endogenous sequence (HRES-1) in SLE. We propose that molecular mimicry between HRES-1 and the small ribonucleoprotein complex initiates the production of autoantibodies, leading to immune complex formation, complement fixation, and pathological tissue deposition.