Chordoma is a rare malignant bone tumor arising from persistent notochordal remnants and is characterized by slow growth, local aggressiveness, and a high rate of recurrence. Surgical resection and radiotherapy remain the mainstays of treatment; however, complete excision is frequently challenging due to the tumor's proximity to critical neurovascular structures, and conventional chemotherapy has shown limited efficacy. Advances in molecular biology have significantly improved understanding of chordoma pathogenesis, revealing key oncogenic drivers such as brachyury (TBXT), receptor tyrosine kinase activation, PI3K/AKT/mTOR signaling, and cell-cycle dysregulation involving CDKN2A and PTEN loss. This review comprehensively summarizes the molecular pathophysiology of chordoma, including genetic, epigenetic, and signaling pathway alterations, and discusses their clinical implications. Emerging molecular-targeted therapies, including tyrosine kinase inhibitors, mTOR inhibitors, CDK4/6 inhibitors, brachyury-targeted approaches, and novel combination strategies, are critically evaluated. Understanding these molecular mechanisms provides a foundation for precision-based therapeutic approaches and highlights future directions aimed at improving disease control, survival outcomes, and quality of life for patients with chordoma.