Abstract: Chordoma is a rare primary bone malignancy, accounting for 1%-4% of all bone primary malignant tumors, which is believed to arise from the remnants of notochord tissues. These tumors typically occur in the axial skeleton, most commonly in the sacrum, skull base and spine. Because of the special location, complete surgical resection and delivery of definitive radiation are not feasible, while conventional chemotherapeutic agents are also not effective. These tumors tend to be locally invasive with a high rate of recurrence. Recent studies have begun to characterize the molecular biology of chordoma. Receptor tyrosine kinase, Akt/mTOR, Ras/MEK/ERK, STAT3 and NF-κB signaling pathways in chordoma have been found. Several molecular targeted drugs for potential clinical therapies have been determined. This article will describe some main signaling pathways in chordoma and the progress of relevant molecular targeted therapy.