Among anti-nuclear antibodies, anti-Sm and anti-RNP antibodies are of the utmost importance in clinical practice. Anti-Sm antibodies are directed against 7 proteins (B/B', D1, D2, D3, E, F, G) that constitute the common core of U1, U2, U4 and U5 small nuclear ribonucleoprotein (snRNP) particles; B/B', D1 and D3 are more frequently targeted. Anti-RNP antibodies react with proteins (70 Kd, A, C) that are associated with U1 RNA and form U1snRNP. Anti-Sm and anti-RNP antibodies are directed towards both discontinuous and linear epitopes which are either contained in the protein sequence or are post-translationally modified. The assays to detect anti-Sm and anti-RNP antibodies are counterimmunoelectrophoresis (CIE), immunoblot, and ELISA, based on purified or recombinant proteins or synthetic peptides. Anti-Sm antibodies are detectable in a percentage of SLE patients comprised between 5 and 30%; they are more prevalent in blacks and because of their high specificity for SLE have been included in the serological criteria for diagnosing the disease.Anti-RNP are detectable in 25-47% of SLE patients; high titers of anti-RNP antibodies are diagnostic of mixed connective tissue disorder (MCTD). The measurement of anti-Sm and anti-RNP antibodies is more important in the diagnosis of SLE than in the follow-up of patients. However, anti-RNP antibodies are more prevalent in patients with Raynaud's phenomenon and are associated with milder renal involvement. On the contrary, anti-Sm antibodies are associated with the severity and the activity of renal involvement. The specificity of anti-Sm antibodies, together with epidemiological data, suggest that Epstein-Barr virus infection has the potential to induce anti-Sm antibodies by molecular mimicry.Anti-nuclear antibodies, a hallmark of the systemic autoimmune diseases, include several populations of antibodies with different specificities. Among them, anti-Sm and anti-RNP antibodies are of the utmost importance in clinical practice; in research, the study of the mechanisms inducing their production has opened up new perspectives and helped to elucidate the pathogenesis of autoimmune disorders.