Transforming growth factor-β (TGF-β) is a profibrotic cytokine involved in the accumulation of extracellular matrix proteins and progression of various fibrotic diseases. TGF-β signaling is transmitted predominantly through cell surface serine/threonine kinase receptors to intracellular mediators known as Smads. The inhibitory Smad7 represses TGF-β signaling by interacting with activated TGFβ receptors, and downregulation of Smad7 facilitates the effects of TGF-β via activation of Smad2 and 3, the receptor-regulated Smads. Activated Smad complexes then translocate into the nucleus to regulate target gene transcription in collaboration with specific transcriptional factors, coactivators, and corepressors. Moreover, several factors involved in this pathway are modulated by the ubiquitinproteasome system. Smad ubiquitination regulatory factors (Smurfs), which are HECT (homologous to E6-AP C-terminus)-type E3 ubiquitin ligases, were recently implicated in regulating the function of Smads in scleroderma and renal fibrosis. In addition, transcriptional corepressors, c-Ski (Sloan-Kettering Institute proto-oncogene) and SnoN (ski-related novel gene N), interact with Smads, and the decreased expression of these proteins also facilitates TGF-β signaling via the Smad proteins. Abnormalities of these regulators of TGF-β signaling may influence organ fibrogenesis, and further studies may reveal new strategies for controlling pathological TGF-β activity.