Chemotherapy is one of the principal treatments for cancer patients in clinics. The chemotherapeutic drugs mostly present a satisfactory effect when they are first exposed to the cancer cells. However, drug resistance always emerges in these tumors. A range of nanodevices or nanostructures with multifunctionalities has been designed to overcome multidrug-resistant cancer cells. Strategies of blocking the drug transporters or inhibiting the expression of P-glycoprotein, integration of multiple drugs within nanomaterials, design of nanodrugs for the targeted killing of cancer stem cells, regulation of the tumor microenvironment, or relieving immunosuppression through nanotechnology-enabled approaches are promising to tackle multidrug resistance of cancer cells. This special issue will cover all aspects of nanotechnology-enabled approaches to treat multidrug-resistant cancer cells.