Human malignant gliomas are highly resistant to current therapeutic approaches. Major signaling pathways that have been identified as playing important roles in glioblastomas are: the PTEN/PI3K/Akt/mTOR and the Ras/Raf/MEK/ERK signaling cascades, which support cell invasion, survival and prevent apoptosis. In the face of tumor resistance to apoptosis, novel agents which can overcome resistance or/and affect cell survival by non-apoptotic mechanisms such as necrosis, senescence, autophagy and mitotic catastrophe, are highly desirable. The present chapter focuses on anti-tumor action of cyclosporin A (CsA) and rapamycin that besides their well known immunosuppressive abilities appear to be multitarget kinase inhibitors and moderately effective anti-tumor agents in glioblastomas in vitro, in vivo and in clinical trials. A compelling evidence shows that cyclosporin A induces growth arrest and programmed cell death in cultured rat and human glioblastoma cells. The molecular mechanism involves accumulation of a cell cycle inhibitor – p21Cip1/Waf1, even in the absence of functional p53 tumor suppressor. In C6 glioma cells with functional TP53 and PTEN tumor suppressors CsA treatment up-regulates fasL expression, activates p53 and intrinsic mitochondrial death pathway, while in human glioblastoma cells with defects in either TP53 or PTEN, none of those effects were observed. Molecular analysis revealed that CsA, trough yet unknown mechanisms, down-regulates PI3K/Akt and mTOR signaling pathways in glioblastoma cells, and interferes with pro-invasive activity of tumor-infiltrating microglia. A systemically applied CsA significantly reduced growth of intracranial gliomas, tumor invasion and angiogenesis. Pharmacological inhibitors of the mTOR pathway: rapamycin, temsirolimus, everolimus and AP23573 were tested as potential targeted drugs in human glioblastoma cultures and in animal models. However, rapamycin and derivatives show moderate efficacy in patients with recurrent glioblastoma multiforme, they deserve further clinical studies, particularly in combination with PI-3 K pathway inhibitors. Defects of innate and adaptive immunity are common in glioblastoma patients contributing to a lack of effective anti-tumor responses. Thus, immunosuppressants such as CsA, rapamycin and its derivatives may be an effective novel strategy to treat drug-resistant gliomas or complement apoptosis based-therapies.