The transforming growth factor-beta (TGF- β) belongs to a superfamily of cytokines that act on protein kinase receptors at the plasma membrane to induce a plethora of biological signals that regulate cell growth and death, differentiation, immune response, angiogenesis and inflammation. Dysregulation of its pathway contributes to a broad variety of pathologies, among them, cancer. TGF-β is an important regulatory tumor suppressor factor in epithelial cells, where it early inhibits proliferation and induces apoptosis. However, tumor cells develop mechanisms to overcome the TGF- β -induced suppressor effects. Once this occurs, cells may respond to this cytokine inducing other effects that contribute to tumor progression. Indeed, TGF-β induces epithelial-mesenchymal transition (EMT), a process that is favored in tumor cells and facilitates migration and invasion. Furthermore, TGF- β mediates production of mitogenic growth factors, which stimulate tumor proliferation and survival. Finally, TGF- β is a well known immunosuppressor and pro-angiogenic factor. Many studies have identified the overexpression of TGF-β1 in various types of human cancer, which correlates with tumor progression, metastasis, angiogenesis and poor prognostic outcome. For these reasons, different strategies to block TGF- β pathway in cancer have been developed and they can be classified in: (1) blocking antibodies and ligand traps; (2) antisense oligos; (3) TRII and/or ALK5 inhibitors; (4) immune response-based strategies; (5) other inhibitors of the TGF- β pathway. In this review we will overview the two faces of TGF- β signaling in the regulation of tumorigenesis and we will dissect how targeting the TGF- β pathway may contribute to fight against cancer.