Scleroderma, also called systemic sclerosis (SSc), is an autoimmune rheumatic disease with high clinical impact and mortality, due to fibrosis and vascular damage in multiple organs. This seminar will highlight the clinical challenge of SSc and give insights into disease biology provided by studying preclinical models, and through high-dimensional analysis of patient biopsies. The presentation will show how progress in understanding pathogenesis is generating a roadmap for development of targeted therapeutics. Current research efforts are harnessing the intrinsic clinical diversity of SSc, and developing outcome-based disease classification, to improve molecular stratification of cases for clinical practice, and in future trials.