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Maheswari Muruganandam, Angie Ariza-Hutchinson, Rosemina A Patel, Wilmer L Sibbitt Jr Department of Internal Medicine, Division of Rheumatology and School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USACorrespondence: Maheswari Muruganandam, Department of Internal Medicine, Division of Rheumatology and School of Medicine, University of New Mexico Health Sciences Center, MSC 10 5550, 5th FL ACC, Albuquerque, NM, 87131, USA, Tel +1 (505) 272-4761, Fax +1 (505) 272-3624, Email mmuruganandam@salud.unm.eduAbstract: Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular damage, vasoinstability, and decreased perfusion with ischemia, inflammation, and exuberant fibrosis of the skin and internal organs. Biomarkers are analytic indicators of the biological and disease processes within an individual that can be accurately and reproducibly measured. The field of biomarkers in SSc is complex as recent studies have implicated at least 240 pathways and dysregulated proteins in SSc pathogenesis. Anti-nuclear antibodies (ANA) are classical biomarkers with well-described clinical classifications and are present in more than 90% of SSc patients and include anti-centromere, anti-Th/To, anti-RNA polymerase III, and anti-topoisomerase I antibodies. Transforming growth factor-β (TGF-β) is central to the fibrotic process of SSc and is intimately intertwined with other biomarkers. Tyrosine kinases, interferon-1 signaling, IL-6 signaling, endogenous thrombin, peroxisome proliferator-activated receptors (PPARs), lysophosphatidic acid receptors, and amino acid metabolites are new biomarkers with the potential for developing new therapeutic agents. Other biomarkers implicated in SSc-ILD include signal transducer and activator of transcription 4 (STAT4), CD226 (DNAX accessory molecule 1), interferon regulatory factor 5 (IRF5), interleukin-1 receptor–associated kinase-1 (IRAK1), connective tissue growth factor (CTGF), pyrin domai