Scleroderma (synonyms: systemic sclerosis, systemic scleroderma) is a systemic disease which affects the skin as well as internal organs such as the lungs, gastrointestinal tract, kidneys, and the heart. Pathogenetically a distinction should be made between uncontrolled formation of extracellular matrix proteins (fibrosis) and vasculopathy. In addition to organ fibrosis, this leads to a clinical picture of vascular manifestations. These include fingertip ulcers, pulmonary arterial hypertension, and acute renal crisis. Localized forms of scleroderma, such as morphea, which do not involve organ complications, should be differentiated from systemic sclerosis. Due to its clinical heterogeneity and high rate of morbidity and mortality, systemic sclerosis poses an enormous diagnostic and therapeutic challenge in everyday clinical practice. This review article summarizes the current status of classification and epidemiology, pathogenesis, and the most important clinical manifestations such as interstitial fibrosis, pulmonary arterial hypertension, acute renal crisis, and peripheral vasculopathy and provides an overview of current and future treatment options.