Study of the clinical associations of antibodies to the soluble antigens Ro/SSA and La/SSB leads to several conclusions. Production of such antibodies are linked to the D locus antigens DR2 and DR3, suggesting involvement of disease susceptibility or immune response genes in the regulation of their synthesis. Genetics therefore provides one of the factors that contribute to the disease expression and the clinical heterogeneity that characterize systemic lupus erythematosus (SLE). The uniform presence of anti-Ro/SSA in neonatal lupus and the almost uniform presence of these antibodies in the vasculitis of Sjögren's syndrome suggest the participation of these antibodies in the immunopathogenesis of these particular clinical manifestations. Finally, identification of the molecular nature of these antigens as RNA-protein conjugates and the ability of the antibodies to La/SSB to bind viral-specific RNA-protein conjugates provide clues that may lead to elucidation of etiologic events in the development of SLE.