Transforming growth factor-β (TGF-β) family members exert their function via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors, including the common mediator Smad4. The dual effects of TGF-β signaling on tumor initiation and progression are cell-specific and yet to be determined under distinct contexts. A number of genetically manipulated mouse models with alterations in the TGF-β pathway genes, particularly the pivotal Smad4, revealed that these genes play crucial functions in maintaining tissue homeostasis and suppressing tumorigenesis. Loss of Smad4 plays a causal role in initiating squamous cell carcinomas of skin and upper digestive tract as well as adenocarcinomas of gastrointestinal tract. However, for some cancers like pancreatic and cholangiocellular carcinomas, Smad4 deficiency does not initiate the tumorigenesis but acts as a promoter to accelerate or synergize the development and progression of cancers that are started by other oncogenic pathways. Intriguingly, emerging evidences from mouse models have highlighted the important roles of non-cell autonomous effects of Smad4-mediated TGF-β signaling in the inhibition of oncogenesis. All these data have greatly deepened our understanding of molecular mechanisms of cell-autonomous and non-cell autonomous effect of Smad4-mediated TGF-β signaling in suppressing carcinogenesis, which may facilitate the development of successful therapies targeting TGF-β signaling for the treatment of human cancers.