Transforming growth factor (TGF)-β is a multifunctional cytokine that contributes to epithelial–mesenchymal transition, tumor development, and metastasis. The tumor microenvironment experiences dynamic changes in composition and mechanical properties, including alignment of matrix components and variations in the stiffness of the stroma, during cancer progression and recent studies have started to elucidate how these changes govern TGFβ signaling. This chapter describes the impact of matrix mechanical properties and cell-generated forces on the activation of TGFβ by cancer-associated fibroblasts and tumor cells. It further reports TGFβ-induced signaling cascades that respond to biophysical cues and that regulate epithelial–mesenchymal transition and tumor progression. Finally, it highlights approaches for targeting biophysical properties of the tumor microenvironment and mechanoresponsive signaling molecules as strategies to block TGFβ-induced tumor progression and metastasis.