Physicians who provide care to patients with systemic sclerosis (SSc, scleroderma) ask themselves several questions: Is SSc the correct diagnosis? Can the disease course be predicted? Is there a greater risk for involvement of certain organs? Can the vital prognosis be predicted? In this brief review, we answer these questions by excerpting data from the literature focused on the 4 major SSc specific autoantibodies (aAbs) to nuclear autoantigens (ANAs): anti-centromere (anti-CENP-B), anti-Th/To, anti-topoisomerase I (anti-topo I) and anti-RNA polymerase III (anti-RNAPIII). The data show that these aAbs are highly valuable as markers for the diagnosis of SSc, as biomarkers for phenotypic subsets and as prognostic markers. We also identify areas for future clinical research.