This review focuses on the application of drug-loaded nanoparticles (NPs), also called therapeutic NPs, to combat cancer chemoresistance. Many cancer patients have encouraging response to first line chemotherapies but end up with cancer progression or cancer recurrence that requires further treatment. Response to subsequent chemotherapies with various agents usually drops significantly due to formidable cancer chemoresistance. A number of mechanisms have been postulated to account for cancer chemoresistance or poor response to chemotherapy. The best studied mechanism of resistance is mediated through the alteration in the drug efflux proteins responsible for the removal of many commonly used anticancer drugs. Therapeutic NPs have emerged as an innovative and promising alternative of the conventional small molecule chemotherapies to combat cancer drug resistance and have shown enhanced therapeutic efficacy and reduced adverse side effects as compared to their small molecule counterparts. Here the possible mechanisms of therapeutic NPs to combat cancer chemoresistance are reviewed, including prolonging drug systemic circulation lifetime, targeted drug delivery, stimuli-responsive drug release, endocytic uptake of drugs and co-delivering chemo-sensitizing agents. We also call attention to the current challenges and needs of developing therapeutic NPs to combat cancer drug resistance.