Patients with brain tumors,specifically,malignant forms such as glioblastoma,medulloblastoma and ependymoma,exhibit dismal survival rates despite advances in treatment strategies.Chemotherapeutics,the primary adjuvant treatment for human brain tumors following surgery,commonly lack efficacy due to either intrinsic or acquired drug resistance.New treatments targeting epigenetic factors are being explored.Post-translational histone modification provides a critical regulatory platform for processes such as chromosome condensation and segregation,apoptosis,gene transcription,and DNA replication and repair.This work reviews how aberrant histone modifications and alterations in histone-modifying enzymes can drive the acquisition of drug resistance in brain tumors.Elucidating these mechanisms should lead to new treatments for overcoming drug resistance. Patients with brain tumors, specifically, malignant forms such as glioblastoma, medulloblastoma and ependymoma, exhibit dismal survival rates with advances in treatment strategies. Chemotherapeutics, the primary adjuvant treatment for human brain tumors following surgery, often lack efficacy due to either intrinsic or acquired drug resistance. New treatments targeting epigenetic factors are being explored. Post-translational histone modification provides a critical regulatory platform for processes such as chromosome condensation and segregation, apoptosis, gene transcription, and DNA replication and repair. This work counts how aberrant histone modifications and alterations in histone-modifying enzymes can drive the acquisition of drug resistance in brain tumors. Elucidating these mechanisms should lead to new treatments for overcoming drug resistance.