Cancer drug resistance is a complex phenomenon that arises from changes in drug targets and is a major challenge in cancer treatment. This review outlines the various mechanisms of drug resistance in cancer, including intrinsic and extrinsic factors, tumor heterogeneity, the tumor microenvironment, cancer stem cells, drug inactivation, multi-drug resistance (MDR), reduced drug absorption, inhibition of cell death (apoptosis), changes in drug metabolism, alterations in drug targets, enhanced DNA repair, gene amplification, and epigenetic changes. These mechanisms contribute to the failure of chemotherapy in treating cancer, particularly in advanced stages involving invasion and metastasis. The review also discusses the role of microRNAs in cancer drug resistance and highlights the potential of epigenetic drugs and combination therapies with established chemotherapeutic agents to overcome resistance. Strategies such as RNA interference (RNAi) using microRNAs (miRNAs) or siRNAs are proposed as novel approaches to suppress drug resistance genes and improve treatment outcomes. The review emphasizes the importance of understanding these mechanisms to develop more effective cancer therapies.Cancer drug resistance is a complex phenomenon that arises from changes in drug targets and is a major challenge in cancer treatment. This review outlines the various mechanisms of drug resistance in cancer, including intrinsic and extrinsic factors, tumor heterogeneity, the tumor microenvironment, cancer stem cells, drug inactivation, multi-drug resistance (MDR), reduced drug absorption, inhibition of cell death (apoptosis), changes in drug metabolism, alterations in drug targets, enhanced DNA repair, gene amplification, and epigenetic changes. These mechanisms contribute to the failure of chemotherapy in treating cancer, particularly in advanced stages involving invasion and metastasis. The review also discusses the role of microRNAs in cancer drug resistance and highlights the potential of epigenetic drugs and combination therapies with established chemotherapeutic agents to overcome resistance. Strategies such as RNA interference (RNAi) using microRNAs (miRNAs) or siRNAs are proposed as novel approaches to suppress drug resistance genes and improve treatment outcomes. The review emphasizes the importance of understanding these mechanisms to develop more effective cancer therapies.