Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin, vascular abnormalities and activation of the immune system. The majority of SSc patients have autoantibodies against nuclear antigens. Among these antibodies against topoisomerase I (topo I) are frequently detected in sera of SSc patients. Since the discovery of these antibodies as immunoglobulins reacting with a 70 kDa nuclear protein (Scl-70), a massive body of clinical and experimental data has been generated. In this review we summarize accumulated evidence about anti-topo I autoantibodies in SSc, including results of epitope mapping studies and investigations on the possible pathogenic role of these antibodies.