In this review we have focused on the utilization of the biocompatible nanomaterials to reverse multidrug resistance (MDR), a major clinical obstacle in cancer therapeutics. Based on the comprehension of the mechanism of MDR and common reversal methods, the strategies and key properties of anti-MDR nanomaterials are explored and described to show how these features could provide the potential therapeutic effects that are not achievable with other modalities. The use of biocompatible nanoparticles with different designs and therapeutic approaches to reverse the MDR of cancer chemotherapeutics offers promising opportunities to benefit patients in the future.