Genetic alterations affecting transforming growth factor β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal (GI) system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the GI tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination.