Cancer is a leading cause of mortality in patients worldwide. Some types of cancer treatment are surgery, chemotherapy, radiation therapy, targeted therapy, immunotherapy, hormone therapy, etc. Therapeutic failure is a result of drug resistance in cancers and this phenomenon is the biggest obstacle in the treatment of cancers. Various mechanisms are involved in chemotherapy resistance of cancers. Some mechanisms for drug resistance are drug efflux, DNA damage repair, epithelial–mesenchymal transition, cell death inhibition, etc. One of the recent and new mechanism of drug resistance is based on non-coding RNAs like lncRNAs, miRNAs, and circRNAs. In this chapter, we discussed drug resistance in cancer focusing on the role of some non-coding RNAs in the resistance of cancers to chemotherapy and some other therapeutic approaches.