TGF-β is a major regulator and driver of many biological processes, but its main function is inhibition of cell cycle progression and apoptosis, thus establishing a tumour-protective effect in early stages of malignant transformation. However, mutational alterations can occur at different levels of the TGF-β signaling cascade. These mutations, combined with the significant influence of the tumour microenvironment on this cascade, can cause a functional shift of TGF-β from being a tumour suppressor to becoming a tumour promoter in more advanced cancers. In most tumours this will ultimately contribute to the formation of metastatic laesions. In the clinical setting of breast cancer, TGF-β plays a significant role in the acquisition of endocrine resistance. Thus, therapeutic intervention of TGF-β signaling might deliver significant benefits in the treatment of cancer. (BELG J MED ONCOL 2012;6:188–193)