The transforming growth factor-β (TGF-β) signalling pathway plays a critical and dual role in the progression of human cancer. During the early phase of tumour progression, TGF-β acts as a tumour suppressor, exemplified by deletions or mutations in the core components of the TGF-β signalling pathway. On the contrary, TGF-β also promotes processes that support tumour progression such as tumour cell invasion, dissemination, and immune evasion. Consequently, the functional outcome of the TGF-β response is strongly context-dependent including cell, tissue, and cancer type. In this review, we describe the molecular signalling pathways employed by TGF-β in cancer and how these, when perturbed, may lead to the development of cancer. Concomitantly with our increased appreciation of the molecular mechanisms that govern TGF-β signalling, the potential to therapeutically target specific oncogenic sub-arms of the TGF-β pathway increases. Indeed, clinical trials with systemic TGF-β signalling inhibitors for treatment of cancer patients have been initiated. However, considering the important role of TGF-β in cardiovascular and many other tissues, careful screening of patients is warranted to minimize unwanted on-target side effects. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.