This review discusses the mechanisms of multidrug resistance (MDR) in cancer chemotherapy, which is responsible for over 90% of cancer patient deaths. MDR mechanisms include enhanced drug efflux, genetic factors (gene mutations, amplifications, and epigenetic alterations), growth factors, increased DNA repair capacity, and elevated metabolism of xenobiotics. The review highlights the latest data on the mechanisms of resistance to anticancer agents used in clinical treatment and the mechanisms of action of novel potential antitumor drugs designed to overcome these resistance mechanisms. Understanding MDR mechanisms and targets of novel chemotherapy agents is crucial for developing new effective strategies in cancer treatment. The review also covers various types of chemotherapeutics, including alkylating agents, antimetabolites, topoisomerase inhibitors, mitotic spindle inhibitors, and others. It discusses the problem of drug resistance in cancer chemotherapy, including enhanced efflux of drugs, genetic factors, epigenetic alterations, growth factors, and increased DNA repair capacity. The review also explores the role of P-glycoprotein (P-gp) in drug resistance and the development of new P-gp inhibitors. Additionally, it discusses the role of gene mutations, amplifications, and epigenetic alterations in cancer chemotherapy resistance. The review also covers the role of growth factors in cancer chemotherapy resistance and the increased DNA repair capacity in cancer cells. Finally, it discusses the elevated metabolism of xenobiotics in cancer cells and its role in drug resistance. The review concludes that understanding the mechanisms of MDR and the targets of novel chemotherapy agents is essential for developing new effective strategies in cancer treatment.This review discusses the mechanisms of multidrug resistance (MDR) in cancer chemotherapy, which is responsible for over 90% of cancer patient deaths. MDR mechanisms include enhanced drug efflux, genetic factors (gene mutations, amplifications, and epigenetic alterations), growth factors, increased DNA repair capacity, and elevated metabolism of xenobiotics. The review highlights the latest data on the mechanisms of resistance to anticancer agents used in clinical treatment and the mechanisms of action of novel potential antitumor drugs designed to overcome these resistance mechanisms. Understanding MDR mechanisms and targets of novel chemotherapy agents is crucial for developing new effective strategies in cancer treatment. The review also covers various types of chemotherapeutics, including alkylating agents, antimetabolites, topoisomerase inhibitors, mitotic spindle inhibitors, and others. It discusses the problem of drug resistance in cancer chemotherapy, including enhanced efflux of drugs, genetic factors, epigenetic alterations, growth factors, and increased DNA repair capacity. The review also explores the role of P-glycoprotein (P-gp) in drug resistance and the development of new P-gp inhibitors. Additionally, it discusses the role of gene mutations, amplifications, and epigenetic alterations in cancer chemotherapy resistance. The review also covers the role of growth factors in cancer chemotherapy resistance and the increased DNA repair capacity in cancer cells. Finally, it discusses the elevated metabolism of xenobiotics in cancer cells and its role in drug resistance. The review concludes that understanding the mechanisms of MDR and the targets of novel chemotherapy agents is essential for developing new effective strategies in cancer treatment.