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Autoimmune connective tissue diseases are clinically variable, making biomarkers desirable for assessing future disease risk, supporting early and accurate diagnosis, monitoring disease activity and progression, selecting therapeutics, and assessing treatment response. Because of their correlations with specific clinical characteristics and often with disease progression, autoantibodies and other soluble mediators are considered potential biomarkers. Additional biomarkers might reflect downstream pathologic processes or appear because of ongoing inflammation and damage. Because of overlap between diseases, some biomarkers have limited specificity for a single autoimmune connective tissue disease. This review describes select current biomarkers that aid in the diagnosis and treatment of several major systemic autoimmune connective tissue disorders: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and anti-neutrophil cytoplasmic antibody–associated vasculitides. Newly proposed biomarkers that target various stages in disease onset or progression are also discussed. Newer approaches to overcome the diversity observed in patients with these diseases and to facilitate personalized disease monitoring and treatment are also addressed.