This comprehensive review explores the mechanisms of cancer drug resistance, particularly in the context of topoisomerase-active drugs such as doxorubicin and topotecan. The review highlights the increasing prevalence of cancer and the significant mortality associated with it, emphasizing the need to understand and address drug resistance. Topoisomerase enzymes, crucial for DNA replication and repair, are targeted by these drugs, but resistance mechanisms, including genetic mutations, epigenetic changes, and cellular adaptations, pose significant challenges. The review delves into the intricate mechanistic aspects of intracellular and extracellular resistance mechanisms, such as ABC transporter overexpression, oxidative stress, DNA damage response, immune heterogeneity, and metabolic reprogramming. It also discusses the potential of combinatorial approaches, combining topo-active drugs with inhibitors of pathways involved in drug resistance, to enhance therapeutic efficacy. The role of glutathione (GSH) in mediating oxidative stress and its impact on drug responsiveness is explored, along with the importance of DNA damage response pathways and metabolic reprogramming in drug resistance. Additionally, the review examines the interaction between immune checkpoint inhibitors and topo-active drugs, as well as the role of cancer stem cells (CSCs) in drug resistance. Finally, it highlights the significance of epigenetic changes and their impact on drug resistance, emphasizing the need for a holistic and interdisciplinary approach to develop more effective cancer therapies.This comprehensive review explores the mechanisms of cancer drug resistance, particularly in the context of topoisomerase-active drugs such as doxorubicin and topotecan. The review highlights the increasing prevalence of cancer and the significant mortality associated with it, emphasizing the need to understand and address drug resistance. Topoisomerase enzymes, crucial for DNA replication and repair, are targeted by these drugs, but resistance mechanisms, including genetic mutations, epigenetic changes, and cellular adaptations, pose significant challenges. The review delves into the intricate mechanistic aspects of intracellular and extracellular resistance mechanisms, such as ABC transporter overexpression, oxidative stress, DNA damage response, immune heterogeneity, and metabolic reprogramming. It also discusses the potential of combinatorial approaches, combining topo-active drugs with inhibitors of pathways involved in drug resistance, to enhance therapeutic efficacy. The role of glutathione (GSH) in mediating oxidative stress and its impact on drug responsiveness is explored, along with the importance of DNA damage response pathways and metabolic reprogramming in drug resistance. Additionally, the review examines the interaction between immune checkpoint inhibitors and topo-active drugs, as well as the role of cancer stem cells (CSCs) in drug resistance. Finally, it highlights the significance of epigenetic changes and their impact on drug resistance, emphasizing the need for a holistic and interdisciplinary approach to develop more effective cancer therapies.