When patients think about cancer therapy, the word they frequently think of is chemotherapy. However, cancer cells become tolerant to pharmaceutical drugs, commonly known as drug resistance, is one of the most challenging problems facing by cancer researchers and patients today. Multiple drug resistance (MDR) has been attributed as the main reason for cancer recurrence and metastasis. Combination chemotherapy was believed as one possible way to overcome or delay the development of tumor. Although, after 50 years of its introduction, the successes achieved with combination chemotherapy had largely saturated. Traditional treatment methods like surgery, and radiotherapy, were clearly inadequate to cure different tumour types. Nanotechnology has become a powerful tool in biomedicine field, and nanoparticles have been opened the gateway for reversing MDR. Compared with “free” drugs, nanomaterials have several advantages containing higher bioavailability, slower drug release, and better treatment outcomes. Furthermore, nanomaterials functionalized with different targeting ligands allow therapeutic drugs to reach tumor sites directly via blood circulation. Thermal, ultrasound, magnetic and light-based responsive nanomaterials have been used for the reversal of drug resistance. In our laboratory, we attempt to develop and explore targeted nanomedicine to overcome MDR in cancer by focusing the blockage of the basic determinants of drug resistance and considering their implications for the development of successful nano-therapeutic strategies. We mainly focus on the development of targeted nanomaterials to block P-glycoprotein (P-gp/ABCB1) and multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) pumps and/or bypass the transporters to reverse drug-efflux-mediated MDR.