The prognosis of patients with glioblastoma, anaplastic astrocytoma, and 
anaplastic oligodendroglioma remains poor despite standard treatment with 
radiotherapy and temozolomide. Molecular targeted therapy holds the promise of 
providing new, more effective treatment options with minimal toxicity. However, 
the development of targeted therapy for gliomas has been particularly 
challenging. The oncogenetic process in such tumors is driven by several 
signaling pathways that are differentially activated or silenced with both 
parallel and converging complex interactions. Therefore, it has been difficult 
to identify prevalent targets that act as key promoters of oncogenesis and that 
can be successfully addressed by novel agents. Several drugs have been tested, 
including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors 
(gefitinib and erlotinib), mammalian target of rapamycin (mTOR) inhibitors 
(temsirolimus and everolimus), and vascular endothelial growth factor receptor 
(VEGFR), protein kinase C-beta, and other angiogenesis pathways inhibitors 
(vatalanib, bevacizumab, and enzastaurin). Although preliminary efficacy results 
of most trials in recurrent disease have fallen short on expectations, 
substantial advances have been achieved by associated translational research. In 
this article, we seek to recapitulate the lessons learned in the development of 
targeted therapy for gliomas, including challenges and pitfalls in the 
interpretation of preclinical data, specific issues in glioma trial design, 
insights provided by translational research, changes in paradigms, and future 
perspectives.