Osteosarcoma is the most common primary solid bone malignancy. The main factor leading to recurrence and metastasis of osteosarcoma is resistance to chemotherapy drugs. Long non-coding RNAs can affect drug resistance in osteosarcoma by regulating epithelial-mesenchymal transition， cell autophagy， apoptosis， drug efflux， and cell cycle， suggesting that long non-coding RNAs may become new targets for drug resistance in osteosarcoma treatment.