Temozolomide (TMZ), an oral alkylating agent, is currently used as a part of standard treatment for glioblastoma multiforme (GBM). GBM is considered one of the most lethal forms of human cancers, and despite recent improvement in cancer therapy, it remains an incurable disease, with a rare long-term survival of the patients due to the rapid emergence of cell clones resistant to treatment. Like other chemotherapeutic agents, resistance to TMZ is the major therapeutic obstacle to effective therapy; thereby, the development of new therapeutic strategies is required to overcome this problem. In the present review, an overview of the recent works on the reduction of TMZ resistance is presented.