Deregulated transforming growth factor-beta (TGF-beta) activity and responses play prominent roles in the pathogenesis of systemic sclerosis (SSc), a chronic and progressive connective tissue disease characterized by fibrosis of the skin and internal organs. Systemic sclerosis has highly heterogeneous clinical manifestations, and patients can be classified into multiple subgroups on the basis of distinct molecular signatures defined by transcriptional profiling of gene expression in target organs. Current research to uncover how TGF-beta regulates fibroblast function opens the door for the discovery of targeted therapies. Anti-fibrotic treatments that selectively block TGF-beta expression, biological activity or intracellular signaling in SSc are currently under development.