The presence of autoantibodies to intracellular molecules is the hallmark immunologic finding of SSc. Recent sophisticated methods have contributed to characterization of unidentified antigens of ANA in sera from patients with SSc. Antibodies to RNA polymerases are the third major SSc-specific ANA, in addition to anti-topo I and anticentromere antibodies, and it is now possible to identify over 85% of SSc patients. These antibodies have proved helpful in diagnosis of this disease. An immunogenetic predisposition to synthesis of the ANAs has been unveiled. Both antigen-driven and molecular mimicry hypotheses have been proposed for ANA production in SSc. Although the role of ANAs in the pathogenesis of SSc is not yet known, it is logical to assume that the origin of ANAs is linked to the causes of this disease because each antibody is associated with its own unique constellation of clinical features.