The transforming growth factorbeta (TGFbeta) superfamily regulates a broad spectrum of biological responses throughout embryonic development and adult life, including cell proliferation and differentiation, epithelial-to-mesenchymal transition, apoptosis, and angiogenesis. TGFbeta members initiate signaling by bringing together a complex of serine/threonine kinase receptors that transmit signals through intracellular Smad proteins. Genetic alterations in numerous components of the TGFbeta signaling pathway have been associated with several human cancers. In addition, tight regulation of TGFbeta signaling is pivotal to the maintenance of homeostasis and the prevention of carcinogenesis. The ubiquitin/proteosome system is one mechanism by which cells regulate the expression and activity of effectors of the TGFbeta signaling cascade. Mounting evidence also suggests that disruption of the ubiquitin-dependent degradation of components of the TGFbeta pathway leads to the development and progression of cancer. Therefore, understanding how these two pathways intertwine will contribute to the advancement of our knowledge of cancer development.