Important clinical advances in the treatment of systemic sclerosis have been made, yet fibrotic disease remains largely untreatable. Optimal design of clinical trials to test new therapeutics for fibrotic disease features has suffered from dual difficulties in patient selection and patient evaluation. Patient selection for entry into trials for treatment of interstitial lung disease and/or skin fibrosis is challenged by the natural history of the disease, which stabilizes in some patients while relentlessly progressing in others, and our lack of good clinical markers to distinguish between these trajectories. Patient evaluation is made difficult, particularly in skin disease, by the inherent difficulty in quantifying the extent of disease. Biomarkers hold the potential to solve many of these problems as surrogate outcome measures and as markers for disease progression. Identified biomarkers may have the potential to graduate to surrogate outcome singly or, more likely, in combination. Predictive biomarkers are still largely unknown.