For patients with osteosarcoma, the use of chemotherapy has improved survival from 11% with surgical resection alone in the 1960s, to 70% by the mid-1980s. However, survival has since plateaued, despite advances in anticancer therapy. Elucidation of the mechanisms of chemoresistance and implementation of strategies to overcome chemoresistance will likely be pivotal to improving survival. In this review, the focus is on the current understanding of the mechanisms of resistance to the most commonly used agents in the treatment of osteosarcoma and the methods employed to overcome chemotherapy resistance.