Systemic sclerosis (SSc) is a clinically heterogeneous orphan disease of unknown etiology and no effective therapy. It is characterized by protean manifestations, an unpredictable disease course and variable outcomes. Clinical manifestations reflect underlying autoimmunity, small vessel vasculopathy and progressive multi-organ fibrosis. Predicting disease progression, pattern and severity of complications and response to therapy in SSc remain major challenges both for the management of patients and for the development of effective disease-modifying therapies. This review summarizes contemporary understanding of novel and emerging biomarkers for SSc. We focus on the development of new classification criteria, the utility of SSc-specific autoantibodies as diagnostic and prognostic markers, and on biomarkers for skin and lung involvement. Finally, we review genome-wide expression analysis as a tool to predict therapeutic responses. We anticipate that the development, validation and application of these biomarkers, singly or more likely in combination, will have a transformative impact in SSc, informing early diagnosis, classification and management, as well as the design, execution and interpretation of clinical trials of novel therapeutic agents.