Transforming growth factor-β (TGFβ) has a crucial role in tissue homeostasis and disruption of the TGFβ pathway has been implicated in many human diseases including cancer. As a potent inhibitor of epithelial cell proliferation, TGFβ is a tumor suppressor. Tumor cells evade the antitumoral effect of TGFβ, either by acquiring somatic mutations that blunt TGFβ signaling or by selectively preventing the cytostatic responses to TGFβ. During tumor progression, TGFβ not only loses the anti-proliferative response but can also become an oncogenic factor. Recent work has provided insights into the specific molecular mechanisms involved in the loss of the TGFβ anti-proliferative response. This review is an overview of the mechanisms that lead to the impairment of the tumor-suppressive function of TGFβ in cancer. The understanding of how the TGFβ signal is disrupted in cancer might facilitate the design and development of rational and successful therapeutic strategies.