This review discusses strategies to overcome chemotherapy resistance in metastatic cancer. Chemotherapy resistance is a major challenge in cancer treatment, with intrinsic and acquired resistance being the two main types. Intrinsic resistance is present before treatment, while acquired resistance develops after treatment. Both types are common in cancer patients. The review explores the molecular mechanisms underlying chemotherapy resistance, including genetic alterations, mutations, epigenetic modifications, altered drug metabolism, and survival pathways. It also discusses strategies to overcome resistance, such as combination therapy, targeted therapies, immunotherapy, and drug repurposing. The review highlights the importance of understanding the molecular mechanisms of resistance and presents various approaches to address this critical issue in treating metastatic cancer. It also discusses the clinical implications of these strategies, including ongoing clinical trials and emerging therapies. The review emphasizes the need for further research to translate laboratory findings into clinical practice and identify new therapeutic avenues. The review concludes that a comprehensive understanding of chemotherapy resistance mechanisms is essential for developing effective treatments for metastatic cancer.This review discusses strategies to overcome chemotherapy resistance in metastatic cancer. Chemotherapy resistance is a major challenge in cancer treatment, with intrinsic and acquired resistance being the two main types. Intrinsic resistance is present before treatment, while acquired resistance develops after treatment. Both types are common in cancer patients. The review explores the molecular mechanisms underlying chemotherapy resistance, including genetic alterations, mutations, epigenetic modifications, altered drug metabolism, and survival pathways. It also discusses strategies to overcome resistance, such as combination therapy, targeted therapies, immunotherapy, and drug repurposing. The review highlights the importance of understanding the molecular mechanisms of resistance and presents various approaches to address this critical issue in treating metastatic cancer. It also discusses the clinical implications of these strategies, including ongoing clinical trials and emerging therapies. The review emphasizes the need for further research to translate laboratory findings into clinical practice and identify new therapeutic avenues. The review concludes that a comprehensive understanding of chemotherapy resistance mechanisms is essential for developing effective treatments for metastatic cancer.