ransforming growth factor-beta (TGF-beta) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-beta and the tissue extracellular matrix components. TGF- is stored in the matrix as part of a large latent complex bound to the latent TGF-beta binding protein (LTBP) and matrix binding of latent TGF-beta complexes, which is required for an adequate TGF-beta function. Once TGF-beta is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer-associated fibroblast (CAF) phenotype. Furthermore, TGF-beta exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-beta and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF beta- chemical inhibitors as a new line of defence against fibrotic disorders or cancer.