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Osteosarcoma is the most common primary bone cancer in young adults and adolescents. Drug resistance is the main cause leading to therapeutical failure. The mechanisms of drug resistance of osteosarcoma have not been fully understood. Notably, recent researches associate microRNA with drug resistance in osteosarcoma cells, raising the awareness that targeting microRNAs may help in chemotherapy success. In this review, we summarize the mechanisms linking microRNAs to drug resistance and ongoing researches on microRNAs in drug response to osteosarcoma. In addition, the therapeutic potential of microRNAs in chemotherapy will also be discussed.