The Smad pathway is involved in transforming growth factor-beta (TGF-beta) signal transduction. The Smad complex binds with the promoter of target gene to modulate gene transcription. Various transcriptional coactivators and corepressors associate directly with Smads for appropriate binding of Smads to target promoters and regulation of Smads transcriptional activities. The ultimate degradation of Smads mediated by the ubiquitin-proteasome pathway (UPP) has been established as a mechanism to shut off the Smad pathway. In addition to the Smad pathway, TGF-beta can also activate other signaling pathway such as the MAPK pathway. The cross-talk of the Smad pathway with other signaling pathways constitutes an important mechanism for the regulatory network of TGF-beta signaling.