Transforming growth factor β (TGF-β) is a pleiotropic cytokine with vital homeostatic functions. Aberrant TGF-β expression is implicated in the pathogenesis of fibrosis in systemic sclerosis (SSc); thus, TGF-β represents a molecular therapeutic target in this disease. Anti-TGF-β monoclonal antibody has been evaluated in a small trial of early SSc, with disappointing results. Antibodies against the αvβ6 integrin that prevent latent TGF-β activation, however, have shown promise in preclinical studies. Small-molecule inhibitors of TGF-β-receptor activity are effective in animal models of fibrosis. Imatinib mesylate and related tyrosine kinase inhibitors also block TGF-β pathways and abrogate fibrotic responses. The blocking of TGF-β activity might lead to spontaneous immune activation, epithelial hyperplasia and impaired wound healing. Loss of immune tolerance is a potential concern in an autoimmune disease such as SSc. Novel insights from microarray-based gene expression analyses and studies of genetic polymorphisms in TGF-β signaling could aid in identifying patients who are most likely to respond to anti-TGF-β treatment. This intervention promises to have a major impact on the treatment of SSc. Concerns regarding efficacy and safety and whether biomarkers can indicate these features, questions regarding appropriate dosing and timing of therapy, and identification of potential responders are critical challenges ahead.