Chordoma is a rare, slow-growing malignant tumor arising from embryonic notochordal remnants, most commonly affecting the skull base, mobile spine, and sacrococcygeal regions. Despite its low incidence, chordoma presents major therapeutic challenges due to its strong propensity for local recurrence, resistance to conventional chemotherapy, and limited systemic treatment options..This review explores the molecular and genetic mechanisms underlying chordomagenesis, emphasizing the central role of brachyury (TBXT) overexpression, chromosomal instability, and deregulation of key oncogenic pathways including RTK/PI3K/AKT/mTOR and MAPK/ERK. Additional mechanisms such as CDKN2A/PTEN loss, JAK/STAT activation, SOX9-mediated stemness, and epigenetic dysregulation contribute to tumor progression and therapeutic resistance and  further summarize current molecularly targeted therapies such as PDGFR, EGFR, and VEGFR inhibitors, mTOR modulators, and CDK4/6 inhibitors highlighting clinical outcomes and ongoing limitations. Collectively, emerging molecular insights support a precision oncology framework integrating targeted drug combinations, immunotherapies, and biomarker-driven strategies to improve progression-free survival and redefine the clinical management of chordoma.