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Multidrug resistance (MDR) is one of the key barriers in chemotherapy, leading to the generation of insensitive cancer cells towards administered therapy. Genetic and epigenetic alterations of the cells are the consequences of MDR, resulted in drug resistivity, which reflects in impaired delivery of cytotoxic agents to the cancer site. Nanotechnology-based nanocarriers have shown immense shreds of evidence in overcoming these problems, where these promising tools handle desired dosage load of hydrophobic chemotherapeutics to facilitate designing of safe, controlled and effective delivery to specifically at tumor microenvironment. Therefore, encapsulating drugs within the nano-architecture have shown to enhance solubility, bioavailability, drug targeting, where co-administered P-gp inhibitors have additionally combat against developed MDR. Moreover, recent advancement in the stimuli-sensitive delivery of nanocarriers facilitates a tumor-targeted release of the chemotherapeutics to reduce the associated toxicities of chemotherapeutic agents in normal cells. The present article is focused on MDR development strategies in the cancer cell and different nanocarrier-based approaches in circumventing this hurdle to establish an effective therapy against deadliest cancer disease.