This review explores the mechanisms of resistance to topoisomerase-active drugs (topo-active drugs) in cancer, emphasizing the complex interplay between cancer cells and these drugs. Topo-active drugs, such as doxorubicin and topotecan, are effective against various cancers but often lead to resistance due to factors like genetic heterogeneity, metabolic reprogramming, and the role of ABC transporters. The review highlights the importance of understanding these resistance mechanisms to develop more effective therapeutic strategies. Topoisomerases, particularly TOPI and TOPII, are crucial enzymes involved in DNA replication and repair. Topo-active drugs inhibit these enzymes, causing DNA damage. However, resistance can develop through various mechanisms, including mutations in topoisomerase genes, altered drug metabolism, and the overexpression of ABC transporters, which expel drugs from cells. Additionally, oxidative stress and the role of glutathione (GSH) in mitigating drug resistance are discussed. The review also addresses the role of cancer stem cells (CSCs) in resistance, as they possess enhanced DNA repair capabilities and can evade immune surveillance. Strategies to target CSCs, such as combining topo-active drugs with immune checkpoint inhibitors, are explored. Furthermore, the review emphasizes the importance of metabolic reprogramming in cancer cells, which can contribute to resistance by altering energy metabolism and supporting tumor growth. The integration of artificial intelligence and machine learning in drug discovery is suggested as a promising approach to identify effective combinations of topo-active drugs and inhibitors. The review concludes that a comprehensive understanding of resistance mechanisms, combined with innovative therapeutic strategies, is essential for improving cancer treatment outcomes.This review explores the mechanisms of resistance to topoisomerase-active drugs (topo-active drugs) in cancer, emphasizing the complex interplay between cancer cells and these drugs. Topo-active drugs, such as doxorubicin and topotecan, are effective against various cancers but often lead to resistance due to factors like genetic heterogeneity, metabolic reprogramming, and the role of ABC transporters. The review highlights the importance of understanding these resistance mechanisms to develop more effective therapeutic strategies. Topoisomerases, particularly TOPI and TOPII, are crucial enzymes involved in DNA replication and repair. Topo-active drugs inhibit these enzymes, causing DNA damage. However, resistance can develop through various mechanisms, including mutations in topoisomerase genes, altered drug metabolism, and the overexpression of ABC transporters, which expel drugs from cells. Additionally, oxidative stress and the role of glutathione (GSH) in mitigating drug resistance are discussed. The review also addresses the role of cancer stem cells (CSCs) in resistance, as they possess enhanced DNA repair capabilities and can evade immune surveillance. Strategies to target CSCs, such as combining topo-active drugs with immune checkpoint inhibitors, are explored. Furthermore, the review emphasizes the importance of metabolic reprogramming in cancer cells, which can contribute to resistance by altering energy metabolism and supporting tumor growth. The integration of artificial intelligence and machine learning in drug discovery is suggested as a promising approach to identify effective combinations of topo-active drugs and inhibitors. The review concludes that a comprehensive understanding of resistance mechanisms, combined with innovative therapeutic strategies, is essential for improving cancer treatment outcomes.