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Colorectal cancer (CRC) being the commonest cancer, is the major cause of mortality and morbidity worldwide. TGF-β pathway is one of the important pathways that play a prominent role in cell proliferation, differentiation, migration and apoptosis. Smad dependent TGF-β signaling cascade is responsible for the regulation and expression of almost 500 odd genes, which in turn play important role in the proper development of intestinal mucosa. Here in this review we have discussed the overall machinery of the TGF-β pathway and the advances in the mutational research on SMAD4 gene in cancers with special look on our own research in CRC cases of Kashmiri population.