Multi-drug resistance (MDR) of cancer cells is a major cause of failure in chemotherapy. To the majority of anti-cancer drugs, tumor cells are able to generate a multi-drug resistance; but there is no common views on the mechanism of MDR. This review summarizes the use of drug delivery system based on nanoparticles to overcome MDR in recent years. Three kinds including non-modified, ligand-modified and multifunctional drug delivery systems are described. Especially, the mechanism of reversing MDR based on nanoparticles is covered. Through efficiently offsetting and antagonizing the action of pumping drugs out of the tumor cells, drug delivery system based on nanoparticles can increase the concentration of the drug in tumors, while reduce the side effects on normal cells and overcome multi-drug resistance. The use of drug-loaded nanoparticles, which combines nanotechnology with the strategy of active and passive targeting administration, has shown significant prospect improving cancer therapy.