Abstract: Glioblastoma(GBM) is the most common malignancy of primary central nervous system in adults. It is considered as the high degree of malignancy with strong invasiveness and easy to relapse, in which the treatment is rather difficult. Gold-standard treatments of GBM include tumor resection, radiotherapy and chemotherapy. Temozolomide(TMZ) is the first-line clinical chemotherapy drug for GBM, and the drug resistance of GBM to TMZ is the main cause leading to the failure of its clinical treatment. At present, the drug resistance mechanisms of TMZ in treatment of GBM mainly include:MicroRNA, DNA repair pathways, cancer stem cells, tumor microenvironment, autophagy of tumor cells and deregulated signalling pathways. This review summarizes the mechanisms of TMZ in treatment of GBM in recent years, and the potential overcoming strategies are discussed.