The TGF-β superfamily plays crucial roles in normal development and physiology. Precise control of TGF-β signaling strength and duration is essential, and dysregulation of this pathway is implicated in the pathogenesis of various human diseases, notably cancer. A hallmark of many cancers is the loss of the TGF-β antiproliferative response, allowing tumor cells to escape growth control. A key mechanism of resistance to TGF-β's cytostatic effects involves inactivating mutations or deletions within the signaling pathway; these are particularly frequent in gastrointestinal and pancreatic cancers. For example, the tumor suppressor Smad4/DPC4, a central mediator of TGF-β signaling, is deleted in over half of pancreatic cancers. However, Smad4 mutations are relatively rare in other cancer types. Our research utilizes functional genomic, proteomic, and cell biological approaches to investigate the regulation of TGF-β's tumor suppressor function in both normal and cancerous cells. We have identified that activation of numerous oncoproteins can induce cellular resistance to TGF-β's growth-inhibitory effects and/or potentiate its metastasis-promoting functions. These novel findings provide conceptual insights into the interplay between oncoproteins and tumor suppressors during tumorigenesis, offering guidance for the rational design of cancer prevention, diagnostic, and therapeutic strategies.