Transforming growth factor-β (TGFβ) signalling provides animal cells with a versatile means of driving developmental programmes and controlling cell behaviour, a role that is evident in the many effects of TGFβ-related cytokines on cell proliferation, differentiation, morphogenesis, tissue homeostasis and regener ation, and the severe diseases that result from their malfunctions.Pioneers in this field in the 1980s welcomed the multi functional nature of TGFβ with mixed feelings. Up to that point, endocrinology was forged on the principle that, by and large, a hormone has one main role and this role only. With TGFβ it was clear from the beginning that this paradigm did not quite fit. The effects of TGFβ were different, even opposite, depending on the cell type and the conditions. The cellular context more than the cytokine dictated the nature of the response. To those intent on elucidating the TGFβ pathway, this contextual functionality was sobering news, as it raised the specter of an impossibly complicated signal transduction process. Yet, the work uncovered a pathway that is relatively simple (in hindsight) and with the power to mediate most effects of any TGFβ family member in any cell type. The TGFβ receptor system, its activation mechanism and SMAD proteins, which function both as substrates for TGFβ receptors and signal transducers, came to light in quick succession. Disease-causing mutations in these components stressed the medical relevance of the new findings. Regulators and complementary pathways were also found. TGFβ target genes that trigger differentiation in stem cells, cell cycle arrest in epithelial cells or homeostatic constraint in immune and vascular cells were identified. Crystal structures of the pathway components were emerging in the blink of an eye as the century was drawing to a close 1 . The TGFβ pathway had been solved, to a first approximation at least.Writing on this subject at the time, the phrase "How cells read TGFβ signals" was picked as a title for two reasons 2 . It was an affirmation that a molecular framework for the exploration of TGFβ biology was firmly in hand. Fleshing out the newly defined pathway became the next task, and the field keenly obliged by identifying additional components, regulators, ancillary pathways and biological effects of the TGFβ family. However, that phrase also implied a challenging question: how does the cellular context determine the response to TGFβ? It was not clear how TGFβ can inhibit cell proliferation but also promote cell growth, enhance stem cell pluripotency but also differentiation, regulate muscle genes in myoblasts and neural genes in neuroblasts, or suppress pre-malignant cells but encourage metastatic ones. These paradoxes suggested that cells read TGFβ signals in ways that could not be explained. Non-canonical TGFβ pathways and malignant switches were explored as alternatives but yielded no answers either. Fifty thousand TGFβ papers later, the old enigma carries on.Interest in solving this puzzle is growing, and it is driven by the importance of TGFβ signalling in medically relevant processes of immunity, inflammation, cancer and fibrosis, as well as bone, muscle, adipose, vascular and haematopoietic homeostasis. At last, recent progress is pointing to a resolution. To cover this progress, the present article provides an overview of the contextual determinants of TGFβ action followed by an update on the signalling, transcriptional and genomic elements of the pathway. Building on this, the final section covers, in broad strokes, the mode of action of TGFβ in various contexts, including embryonic stem (ES) cells, lineage-committed progenitors, cells undergoing epithelial-mesenchymal transition (EMT), induced pluripotent stem (iPS) cells, differentiated cells and cells at various stages of malignancy.