Multidrug resistance (MDR), which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence, has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades. Several mechanisms of overcoming drug resistance have been postulated. Well known P-glycoprotein (P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure. Innovative theranostic (therapeutic and diagnostic) strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits. In this review, we discuss the mechanisms of drug efflux-mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome.