The current approach to diagnosis and management of the rare disease systemic sclerosis (SSc) is based on American College of Rheumatology criteria with low sensitivity and few validated recommendations for the therapy of the disease and its manifold organ manifestations. To overcome these shortcomings, the DeSScipher project will use the multinational, prospective and open EUSTAR (Scleroderma Trials and Research group of the European League Against Rheumatism) SSc cohort based on the established MEDSonline database which covers >30 data items and will evolve into a multimodular tool to answer step-by-step all immanent questions in a long-term setting according to the nature of the disease. The resulting progress will address functionally disabling manifestations affecting the hands (digital ulcers and arthritis), and compare the efficacy and safety of off-label drugs in the treatment of vital organ manifestations. Specifically, the DeSScipher project will evaluate (i) the utility of a combination of easy-to-perform clinical and laboratory investigations in combination with capillaroscopy for identifying SSc patients at risk for the development of digital ulcers at an early stage (ii) the prevention and treatment of digital ulcers and hand arthritis in order to improve long-term disability and quality of life, (iii) the efficacy of different immunosuppressive agents in attenuating or inhibiting pulmonary fibrosis, (iv) the optimal treatment options for reducing morbidity and mortality of pulmonary hypertension and severe heart disease in SSc. Based on the results of these observational trials, the DeSScipher project will develop evidence-based clinical guidelines for the future management of adult and juvenile SSc to be disseminated widely and rapidly to physicians and patients. Novel outcome measures will also be provided as a basis for future clinical trials.