Scleroderma, or systemic sclerosis, is a clinically heterogeneous disease characterized by fibroproliferative vasculopathy, tissue fibrosis affecting the skin and internal organs, and autoimmune activation. Many biomarker candidates have been identified in the past two decades; however, fully validated measures are still lacking with regard to aiding in the early diagnosis and reflecting the disease activity, severity, prognosis, and response to therapy. An ideal biomarker should be highly sensitive and specific, reflecting the current status of disease; should be related to the disease activity and/or severity in accordance with the clinical evolution; should anticipate clinical changes before they occur; and should add independent information about the risk or prognosis that is reproducible and feasible. This review focuses on the most recent and innovative approaches to identify biomarkers, such as extensive gene expression analysis and proteomics, and on markers and surrogate outcome measures closer to clinical practice, and attempts to evaluate them through the OMERACT (Outcome Measures in Rheumatology Clinical Trials) filter.