Systemic sclerosis is a complex autoimmune disease characterized by a chronic and frequently progressive course and by extensive patient-to-patient variability. Like other autoimmune diseases, systemic sclerosis occurs more frequently in women, with a peak of onset in the fifth decade of life. The exact cause of systemic sclerosis remains elusive but is likely to involve environmental factors in a genetically primed individual. Pathogenesis is dominated by vascular changes; evidence of autoimmunity with distinct autoantibodies and activation of both innate and adaptive immunity; and fibrosis of the skin and visceral organs that results in irreversible scarring and organ failure. Intractable progression of vascular and fibrotic organ damage accounts for the chronic morbidity and high mortality. Early and accurate diagnosis and classification might improve patient outcomes. Screening strategies facilitate timely recognition of life-threatening complications and initiation of targeted therapies to halt their progression. Effective treatments of organ-based complications are now within reach. Discovery of biomarkers - including autoantibodies that identify patient subsets at high risk for particular disease complications or rapid progression - is a research priority. Understanding the key pathogenetic pathways, cell types and mediators underlying disease manifestations opens the door for the development of targeted therapies with true disease-modifying potential. For an illustrated summary of this Primer, visit: http://go.nature.com/lchkcA.