Transdifferentiation of epithelial cells into cells with mesenchymal properties and appearance, that is, epithelial–mesenchymal transition (EMT), is essential during development, and occurs in pathological contexts, such as in fibrosis and cancer progression. Although EMT can be induced by many extracellular ligands, TGF-β and TGF-β-related proteins have emerged as major inducers of this transdifferentiation process in development and cancer. Additionally, it is increasingly apparent that signaling pathways cooperate in the execution of EMT. This update summarizes the current knowledge of the coordination of TGF-β-induced Smad and non-Smad signaling pathways in EMT, and the remarkable ability of Smads to cooperate with other transcription-directed signaling pathways in the control of gene reprogramming during EMT.