Glioblastoma remains a tumor with a dismal prognosis because of failure of current treatment. Glioblastoma cells with stem cell (GSC) properties survive chemotherapy and give rise to tumor recurrences that invariably result in the death of the patients. Here we summarize the current knowledge on chemoresistance of malignant glioma with a strong focus on GSC. Chemoresistant GSC are the most likely cause of tumor recurrence, but it remains controversial if GSC and under which conditions GSC are more chemoresistant than non-GSC within the tumor. Regardless of this uncertainty, the chemoresistance varies and it is mainly mediated by intrinsic factors. O6-methyl-guanidine methyltransferase (MGMT) remains the most potent mediator of chemoresistance, but disturbed mismatch repair system and multidrug resistance proteins contribute substantially. However, the intrinsic resistance by MGMT expression is regulated by extrinsic factors like hypoxia increasing MGMT expression and thereby resistance to alkylating chemotherapy. The search of new biomarkers helping to predict the tumor response to chemotherapy is ongoing and will complement the already known markers like MGMT.