The article by Joan Massagué provides an overview of the context-dependent nature of TGFβ signaling, highlighting its multifunctional role in various biological processes and diseases. TGFβ signaling, which involves the activation of SMAD proteins, is a key regulator of gene expression and cell behavior. The context in which TGFβ acts, including the cell type, developmental stage, and environmental cues, significantly influences the cellular response. The article discusses the three main determinants of TGFβ action: the extracellular and intracellular composition of the signal transduction system, the co-operating factors that regulate transcription, and the epigenetic landscape of the cell. Recent progress in understanding the signaling machinery, transcriptional and genomic elements, and the mode of action of TGFβ in various contexts, such as embryonic stem cells, lineage-committed progenitors, epithelial–mesenchymal transition, induced pluripotent stem cells, differentiated cells, and cancer, is reviewed. The article also explores non-canonical TGFβ pathways and their role in malignant switches. Finally, it outlines future research directions, emphasizing the need for structural analysis, quantitative studies, and a deeper understanding of TGFβ's role in cell death pathways and cancer progression.The article by Joan Massagué provides an overview of the context-dependent nature of TGFβ signaling, highlighting its multifunctional role in various biological processes and diseases. TGFβ signaling, which involves the activation of SMAD proteins, is a key regulator of gene expression and cell behavior. The context in which TGFβ acts, including the cell type, developmental stage, and environmental cues, significantly influences the cellular response. The article discusses the three main determinants of TGFβ action: the extracellular and intracellular composition of the signal transduction system, the co-operating factors that regulate transcription, and the epigenetic landscape of the cell. Recent progress in understanding the signaling machinery, transcriptional and genomic elements, and the mode of action of TGFβ in various contexts, such as embryonic stem cells, lineage-committed progenitors, epithelial–mesenchymal transition, induced pluripotent stem cells, differentiated cells, and cancer, is reviewed. The article also explores non-canonical TGFβ pathways and their role in malignant switches. Finally, it outlines future research directions, emphasizing the need for structural analysis, quantitative studies, and a deeper understanding of TGFβ's role in cell death pathways and cancer progression.