Transforming growth factor-beta (TGF-beta) signaling mainly relies on the TGF-beta receptor-Smad pathway. Meanwhile, TGF-beta binding to its receptors initiates the degradation of several key components of its signaling pathway. The degradation of these components, including both positive and negative transducers, is mediated by the ubiquitin-proteasome system. Inhibition of the proteasome activity causes accumulation of these components in the cells and modulates TGF-beta signaling in a time-dependent and gene-specific manner. The accelerated degradation of TGF-beta signaling components via the proteasome system has been found in a number of tumors, indicating that dysregulated proteasomal degradation is a novel pathway how tumor cells silence TGF-beta signaling.