Glioblastoma (GBM) is the most common and malignant primary brain tumor. Despite recent advances in treatment regimens, the prognosis of patients remains poor. Although different combined therapies of surgery, radiation and chemotherapy are being essayed in order to cope with resistance and relapse to prolong survival time and reach complete remission, these have still demonstrated equivocal significant benefit. In chemotherapy era, this shortcoming lead investigators to design new antineoplastic agents. Although most of them reached their aim, one side of the coin shows that this process from bench to in vivo and phase trials take a lot of time and money resulting in more death and the formation and/or incidence of economic crisis. Another side of the coin is lack of stability and/or quality of patients' social life during chemotheraphy due to psychiatric disorders. Two parts of the coin are apart so they are not valuable. Consequently, investigators start to search whether commonly and effectively used non antineoplastic drugs for a long time in clinic has anti-neoplastic effects and/or has ability to potentiate antineoplastic drugs cytotoxicity or not. An antidepressant chlorimipramine (CIMP) has been being involved in these trials and proposed as a promising antineoplastic agent. In addition, investigators chose to experience current antineoplastic agents which their success were proved at specific cancer types for another cancer types such as an antileukemic agent imatinib mesylate (IM) in GBM. This chapter focuses on GBM, and the roles of IM and CIMP in the treatment of GBM.