This article reviews the clinical background and significance of selected biomarkers that have been studied in relation to systemic sclerosis, or scleroderma, a devastating connective tissue disease whose morbidity and mortality are often related to pulmonary complications. Interstitial lung disease is the most common pulmonary manifestation in systemic sclerosis, and the search for a noninvasive biomarker to assess and monitor patients and their lung disease is a nascent and expending field of study. In this article, we examine the background and significance of a variety of selected biomarkers and assess their role in relation to systemic sclerosis–related interstitial lung disease.