The TGF-β family, consisting of three isoforms (TGF-β1, 2, and 3), plays crucial roles in cell growth, survival, immune response, and differentiation. However, their dysregulated expression contributes to various diseases, including cancer and fibrosis. Despite extensive efforts to develop TGF-β inhibitors, challenges remain in effectively targeting pathological functions while preserving physiological roles. Many existing approaches target all three isoforms collectively, failing to specifically address deregulated ones. This review provides a historical overview of TGF-β research, emphasizing isoform-specific functions and disease implications. It highlights the need for more targeted therapeutic strategies, particularly isoform-selective antagonists, to enhance the effectiveness of TGF-β-targeted cancer therapies. The review also discusses the molecular intricacies of TGF-β ligands, their regulation, and the mechanisms underlying their dysregulation in cancer. Key findings include the differential regulation and functions of each TGF-β isoform, the role of specific regulators, and the importance of understanding these complexities for effective targeted therapeutics.The TGF-β family, consisting of three isoforms (TGF-β1, 2, and 3), plays crucial roles in cell growth, survival, immune response, and differentiation. However, their dysregulated expression contributes to various diseases, including cancer and fibrosis. Despite extensive efforts to develop TGF-β inhibitors, challenges remain in effectively targeting pathological functions while preserving physiological roles. Many existing approaches target all three isoforms collectively, failing to specifically address deregulated ones. This review provides a historical overview of TGF-β research, emphasizing isoform-specific functions and disease implications. It highlights the need for more targeted therapeutic strategies, particularly isoform-selective antagonists, to enhance the effectiveness of TGF-β-targeted cancer therapies. The review also discusses the molecular intricacies of TGF-β ligands, their regulation, and the mechanisms underlying their dysregulation in cancer. Key findings include the differential regulation and functions of each TGF-β isoform, the role of specific regulators, and the importance of understanding these complexities for effective targeted therapeutics.