Cancer remains a leading cause of death worldwide, and chemotherapy is the primary method for cancer treatment. However, multidrug resistance (MDR) in cancer cells is responsible for over 90% of deaths in patients receiving traditional chemotherapeutics. MDR mechanisms include enhanced drug efflux, increased DNA repair capacity, genetic factors, and elevated metabolism of xenobiotics. This review aims to present the latest data on cellular resistance to anticancer agents and the mechanisms of action of novel potential antitumor drugs designed to overcome these resistance mechanisms. The paper discusses the classification of chemotherapeutics, their mechanisms of action, and the impact of MDR on treatment efficacy. It also highlights the role of P-glycoprotein (P-gp) in drug efflux and the development of P-gp inhibitors. Additionally, the paper explores genetic factors such as gene mutations, amplifications, and epigenetic alterations, which contribute to MDR. The influence of growth factors and increased DNA repair capacity on chemoresistance is also discussed. Finally, the paper reviews strategies to overcome MDR, including the use of novel compounds and inhibitors targeting specific molecular targets. Understanding these mechanisms and targets can guide future research in developing more effective cancer treatment strategies.Cancer remains a leading cause of death worldwide, and chemotherapy is the primary method for cancer treatment. However, multidrug resistance (MDR) in cancer cells is responsible for over 90% of deaths in patients receiving traditional chemotherapeutics. MDR mechanisms include enhanced drug efflux, increased DNA repair capacity, genetic factors, and elevated metabolism of xenobiotics. This review aims to present the latest data on cellular resistance to anticancer agents and the mechanisms of action of novel potential antitumor drugs designed to overcome these resistance mechanisms. The paper discusses the classification of chemotherapeutics, their mechanisms of action, and the impact of MDR on treatment efficacy. It also highlights the role of P-glycoprotein (P-gp) in drug efflux and the development of P-gp inhibitors. Additionally, the paper explores genetic factors such as gene mutations, amplifications, and epigenetic alterations, which contribute to MDR. The influence of growth factors and increased DNA repair capacity on chemoresistance is also discussed. Finally, the paper reviews strategies to overcome MDR, including the use of novel compounds and inhibitors targeting specific molecular targets. Understanding these mechanisms and targets can guide future research in developing more effective cancer treatment strategies.