The development of multidrug resistance (MDR) to chemotherapy is a major obstacle for the successful treatment of cancer. A number of mechanisms have been postulated to account for MDR in cancer. The most common and best-studied mechanism of resistance is mediated through the drug efflux protein P-glycoprotein (P-gp), which is overexpressed in drug-resistant cancer cells and is responsible for the removal of many chemotherapeutic agents. Therapeutic nanoparticles (NPs) have emerged as an innovative and promising option to combat P-gp-mediated MDR and have shown enhanced therapeutic efficacy and reduced toxicity compared to their small molecule counterparts. This review focuses on recent studies using therapeutic NPs to circumvent P-gp-mediated MDR in cancer therapy. The advantages and strategies by which therapeutic NPs were used to overcome P-gp-mediated MDR in cancer are discussed.