Cancer is a highly heterogeneous disease at intra/inter patient levels and known as the leading cause of death worldwide. A variety of mono and combinational therapies including chemotherapy have been evolved over the years for its effective treatment. However, advent of chemotherapeutic resistance or multidrug resistance (MDR) in cancer is a major challenge researchers are facing in cancer chemotherapy. MDR is a complex process having multifaceted non-cellular or cellular-based mechanisms. Research in the area of cancer nanotechnology over the past two decade has now proven that the smartly designed nanoparticles help in successful chemotherapy by overcoming the MDR and preferentially accumulate in the tumor region by means of active and passive targeting therefore reducing the offtarget accumulation of payload. Many of such nanoparticles are in different stages of clinical trials as nanomedicines showing promising result in cancer therapy including the resistant cases. Nanoparticles as chemotherapeutics carriers offer the opportunity to have multiple payload of drug and or imaging agents for combinational and theranostics therapy. Moreover, nanotechnology further bring in notice the new treatment strategies such as combining the NIR, MRI and HIFU in cancer chemotherapy and imaging. Here, we discussed the cellular/non-cellular factors constituting the MDR in cancer and the role of nanomedicines in effective chemotherapy of MDR cases of cancers. Moreover, recent advancements like combinational payload delivery and combined physical approach with nanotechnology in cancer therapy have also been discussed.