Invasion and metastasis are the most lethal characteristics of cancer and the leading causes of cancer-related death. Transforming growth factor (TGF)-β is a multifunctional cytokine that normally functions to prevent the uncontrolled proliferation of epithelial, endothelial and hematopoietic cells. Quite dichotomously, however, aberrant genetic or epigenetic events often negate the cytostatic function of TGF-β in these cells, leading to tumor formation. Once freed from the growth-inhibitory effects of TGF-β, cancer cells acquire the ability to proliferate, invade and metastasize when stimulated by TGF-β. A thorough understanding of the molecular mechanisms underlying these paradoxical functions of TGF-β remains elusive. Here, the authors review the tumor-suppressing and -promoting activities of TGF-β and discuss the potential use and targeting of the TGF-β-signaling system to prevent the progression and acquisition of metastatic phenotypes by human malignancies.