Therapeutic anticytokine approaches have revolutionized the treatment of chronic inflammatory diseases, and targeting of transforming growth factor-beta (TGF-beta), a key factor in the pathogenesis of fibrosis, is undergoing evaluation for scleroderma. Several considerations dictate a cautious approach to anti-TGF-beta interventions. These include the possibility of multiple cytokines having overlapping roles in the pathogenesis of fibrosis and concerns that, in light of its numerous homeostatic functions, blocking TGF-beta may have serious adverse consequences. Furthermore, as autonomously activated cells, scleroderma fibroblasts may be unresponsive to blockade of TGF-beta signaling. This article reviews the experimental evidence underlying these concerns, and indicates rational approaches to addressing and overcoming them.