The Wnt/β-catenin signaling pathway plays a critical role in cancer development and progression by regulating stem cell renewal, proliferation, and differentiation. Targeting this pathway has shown therapeutic potential in various cancers. Key components of the pathway, including the Wnt ligand/receptor interface, β-catenin destruction complex, and TCF/β-catenin transcription complex, are being targeted with inhibitors, antagonists, and activators. Preclinical and clinical studies have identified several agents, such as PORCN inhibitors (e.g., WNT974, CGX1321), Wnt/FZD antagonists (e.g., Ipafricept, OMP-18R5), and tankyrase inhibitors (e.g., XAV939, IWR-1), which show promise in cancer treatment. Additionally, natural compounds and repurposed drugs, such as curcumin, 3,3'-diindolylmethane, and niclosamide, have demonstrated anti-tumor effects by modulating the Wnt/β-catenin pathway. Cancer stem cells (CSCs) are particularly vulnerable to Wnt/β-catenin pathway inhibitors, as their self-renewal and survival depend on this pathway. However, challenges remain in developing safe and effective targeted therapies, including off-target effects, toxicity, and resistance. Further research is needed to optimize targeted agents and improve clinical outcomes in cancer treatment.The Wnt/β-catenin signaling pathway plays a critical role in cancer development and progression by regulating stem cell renewal, proliferation, and differentiation. Targeting this pathway has shown therapeutic potential in various cancers. Key components of the pathway, including the Wnt ligand/receptor interface, β-catenin destruction complex, and TCF/β-catenin transcription complex, are being targeted with inhibitors, antagonists, and activators. Preclinical and clinical studies have identified several agents, such as PORCN inhibitors (e.g., WNT974, CGX1321), Wnt/FZD antagonists (e.g., Ipafricept, OMP-18R5), and tankyrase inhibitors (e.g., XAV939, IWR-1), which show promise in cancer treatment. Additionally, natural compounds and repurposed drugs, such as curcumin, 3,3'-diindolylmethane, and niclosamide, have demonstrated anti-tumor effects by modulating the Wnt/β-catenin pathway. Cancer stem cells (CSCs) are particularly vulnerable to Wnt/β-catenin pathway inhibitors, as their self-renewal and survival depend on this pathway. However, challenges remain in developing safe and effective targeted therapies, including off-target effects, toxicity, and resistance. Further research is needed to optimize targeted agents and improve clinical outcomes in cancer treatment.