Cancer is a potentially life-threatening malignancy with a high global mortality rate. In 2024, an estimated 611,720 individuals are projected to die from cancer in the United States. Lung and bronchus cancer are expected to account for the highest number of deaths, with 125,070 fatalities, nearly three times the 53,010 deaths anticipated from colorectal cancer, the second leading cause of cancer mortality. Pancreatic cancer ranks third, with an estimated 51,750 deaths. Oncology research is focused on molecular mechanism, cancer pathogenesis, and progression to develop more accurate diagnostics and effective treatments. Transforming growth factor-β (TGF-β) is a multifunctional cytokine and plays a crucial factor in embryonic development and tissue homeostasis. Dysregulation of TGF-β signaling can result in a variety of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. The TGF-β1 activation in canonical and noncanonical signaling and mutations in TGF-β1 and its receptors are associated with the oncogenic activity. In the early stages of cancer, TGF-β plays a tumor suppressor role by inhibiting cell cycle progression and promoting apoptosis in epithelial cells. In the later stages, TGF-β1 is associated with tumor progression, enhanced cell motility, invasiveness, and metastasis. Also, TGF-β1 is involved in the tumor microenvironment and promotes epithelial-to-mesenchymal transition (EMT). Recent studies have shown that TGF-β is involved in the stimulation of extracellular matrix deposition, angiogenesis, and antitumor immune response. The pro-oncogenic roles of TGF-β have garnered significant attention because they offer a potential therapeutic target for cancer treatment. However, the critical role of TGF-β in maintaining tissue homeostasis poses a challenge in targeting this pathway. This chapter summarizes the role of TGF-β1 signaling in various cancers and current therapeutic interventions targeting TGF-β. Based on recent research, several drugs were developed based on target TGF-β1 and are in nonclinical or early clinical stages of investigation.