This comprehensive review addresses the challenges of chemotherapy resistance in metastatic cancer and explores strategies to overcome it. The manuscript begins by highlighting the clinical significance of chemotherapy resistance and the current challenges in treating metastatic cancer. It delves into the molecular mechanisms underlying chemotherapy resistance, including genetic alterations, mutations, epigenetic modifications, altered drug metabolism, and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death. The review then examines various strategies to overcome chemotherapy resistance, such as combination therapy, targeted therapies, immunotherapeutic approaches, and repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. The manuscript also discusses early detection and monitoring of chemotherapy drug resistance, rational drug design, predictive biomarkers, and the importance of lifestyle modifications and supportive therapies. Finally, it outlines the clinical implications of the discussed strategies, including insights into ongoing clinical trials and emerging therapies. The review emphasizes the importance of understanding the molecular mechanisms of resistance and presents a range of approaches to address this critical issue in treating metastatic cancer.This comprehensive review addresses the challenges of chemotherapy resistance in metastatic cancer and explores strategies to overcome it. The manuscript begins by highlighting the clinical significance of chemotherapy resistance and the current challenges in treating metastatic cancer. It delves into the molecular mechanisms underlying chemotherapy resistance, including genetic alterations, mutations, epigenetic modifications, altered drug metabolism, and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death. The review then examines various strategies to overcome chemotherapy resistance, such as combination therapy, targeted therapies, immunotherapeutic approaches, and repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. The manuscript also discusses early detection and monitoring of chemotherapy drug resistance, rational drug design, predictive biomarkers, and the importance of lifestyle modifications and supportive therapies. Finally, it outlines the clinical implications of the discussed strategies, including insights into ongoing clinical trials and emerging therapies. The review emphasizes the importance of understanding the molecular mechanisms of resistance and presents a range of approaches to address this critical issue in treating metastatic cancer.