Abstract: Chemotherapeutic agents along with other treatments, such as chemotherapy and radiotherapy, have made significant contributions to cancer therapy, however multidrug resistance (MDR) in tumor remains an important developmental barrier to efficient chemotherapy. In recent research, there is increasing evidence that nitric oxide (NO) has the potential to overcome MDR. Unlike other chemosensitizers that ameliorate MDR but are potentially toxic, NO is endogenous and biocompatible molecule, which makes it even more promising as a cancer therapeutic. Nanoparticle-based drug delivery systems not only facilitate the delivery of multiple therapeutic agents, but also promote the avoidance of MDR, which are promising to both efficient delivery of NO and anti-cancer drugs in combination. Therefore, this review will discuss the mechanisms how NO reverse MDR and the recent advances in the application of NO functionalized nanoparticles for anticancer drug delivery.