Systemic lupus erythematosus (SLE) and related diseases are characterized by circulating autoantibodies to defined intracellular targets. Among the earliest identified autoantibodies were those directed to components of U2-U6 small nuclear ribonucleoproteins (snRNPs) known as Smith (Sm) antigen, which are highly specific for SLE. The Sm-antigen is composed of at least nine different polypeptides with molecular weights ranging from 9 to 29.5 kDa (B (B1, 28 kDa), B' (B2, 29 kDa), N (B3, 29.5 kDa), D1 (16 kDa), D2 (16.5 kDa), D3 (18 kDa), E (12 kDa), F (11 kDa), and G (9 kDa)). All of the nine core proteins, but most frequently the B and D polypeptides, are targets of the anti-Sm autoimmune response. However, since SmBB' and U1 specific RNPs share the cross-reactive epitope motif PPPGMRPP, SmD is regarded as the most SLE specific Sm-antigen. It has been shown that the polypeptides D1, D3, and BB' contain symmetrical dimethylarginine, constituting a major autoepitope within the C-terminus of SmD1 and SmD3. Several synthetic peptides have been used for the detection of anti-Sm antibodies and thus for the diagnosis of SLE. Anti-Sm antibodies have been reported to occur later than other SLE associated autoantibodies and, on average, around 1 year before the clinical onset of SLE. The present review provides a comprehensive summary on the history of anti-Sm antibodies and their use as biochemical tools to study cellular processes and as biomarker in the diagnosis of SLE. Additionally, a meta-analysis focused on recent data analyzes the prevalence of anti-Sm antibodies in SLE.