Inefficiencies in systemic drug delivery and tumor residence as well as micro-environmental selection pressures contribute to the development of multidrug resistance (MDR) in cancer. Characteristics of MDR include abnormal vasculature, regions of hypoxia, up-regulation of ABC-transporters, aerobic glycolysis, and an elevated apoptotic threshold. Nano-sized delivery vehicles are ideal for treating MDR cancer as they can improve the therapeutic index of drugs and they can be engineered to achieve multifunctional parameters. The multifunctional ability of nanocarriers makes them more adept at treating heterogeneous tumor mass than traditional chemotherapy. Nanocarriers also have preferential tumor accumulation via the EPR effect; this accumulation can be further enhanced by actively targeting the biological profile of MDR cells. Perhaps the most significant benefit of using nanocarrier drug delivery to treat MDR cancer is that nanocarrier delivery diverts the effects of ABC-transporter mediated drug efflux; which is the primary mechanism of MDR. This review discusses the capabilities, applications, and examples of multifunctional nanocarriers for the treatment of MDR. This review emphasizes multifunctional nanocarriers that enhance drug delivery efficiency, the application of RNAi, modulation of the tumor apoptotic threshold, and physical approaches to overcome MDR.