TGF-β plays an essential role in maintaining tissue homeostasis through its ability to induce cell cycle arrest, differentiation and apoptosis, and to preserve genomic stability. Thus, TGF-β is a potent anticancer agent that prohibits the uncontrolled proliferation of epithelial, endothelial and hematopoietic cells. Interestingly, tumorigenesis typically elicits aberrations in the TGF-β signaling pathway that engenders resistance to the cytostatic activities of TGF-β, thereby enhancing the development and progression of human malignancies. Moreover, these genetic and epigenetic events conspire to convert TGF-β from a suppressor of tumor formation to a promoter of their growth, invasion and metastasis. The dichotomous nature of TGF-β during tumorigenesis is known as the ‘TGF-β paradox’, which remains the most critical and mysterious question concerning the physiopathological role of this multifunctional cytokine. Here we review recent findings that directly impact our understanding of the TGF-β paradox and discuss their importance to targeting the oncogenic activities of TGF-β in developing and progressing neoplasms.