Glioma, especially glioblastoma multiforme (GBM), has become one of the major clinical challenges in the field of neurooncology due to its high invasiveness and significant multidrug resistance (MDR). The mechanism of drug resistance is complex and involves the synergy of many factors, including the overexpression of MDR related transporters such as P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP), the characteristics of tumor stem cells, and the influence of tumor microenvironment (especially hypoxia). In addition, abnormally activated signaling pathways (such as Hippo pathway), abnormal regulation of non coding RNA and mitochondrial dysfunction also contribute to treatment failure. This article reviews the molecular research progress in the mechanism of drug resistance in glioma in recent years, focusing on the dynamic regulation of MDR protein, the drug resistance mediated by tumor stem cells, the impact of tumor microenvironment on drug efficacy, and the role of signaling pathways and non coding RNA in the development of drug resistance. At the same time, this paper also discusses the emerging strategies of drug delivery system and combination therapy based on nanotechnology. Through the systematic integration of existing studies, the aim is to deeply analyze the mechanism of drug resistance, provide theoretical basis and direction for the development of more effective treatment, and ultimately help improve the clinical prognosis.