Transforming growth factor-β (TGFβ) signaling regulates multiple cellular processes, including extracellular matrix production, cell growth, apoptosis and differentiation. Dysfunction of TGFβ signaling has been implicated in various human disorders ranging from vascular diseases to cancer. TGFβ signaling is negatively regulated by the transcriptional repressor TGFβ-induced factor 1 (TGIF1). The tumor suppressor Fbxw7 is the substrate-recognition factor of a ubiquitin ligase that targets multiple proteins for degradation, including c-Myc, cyclin E, c-Jun and Notch. Here, we describe that TGIF1 is targeted for degradation by Fbxw7 in a phosphorylation-dependent manner. Inactivation of Fbxw7 results in the accumulation of phosphorylated TGIF1 molecules and repression of TGFβ-dependent transcription. Cancer cell lines with inactivating mutations in Fbxw7 show enhanced levels of TGIF1 and attenuated TGFβ-dependent signaling. Importantly, inactivation of Fbxw7 attenuates TGFβ-dependent regulation of cell growth and migration. Taken together, our results suggest that Fbxw7 is a novel regulator of TGFβ signaling.