The identification of molecular markers associated with tumor but not with normal tissue has allowed the development of highly specific, targeted therapies for the treatment of cancer. Over the last several years, tremendous advances in our understanding of the genetic and molecular changes involved in the progression of malignant gliomas have triggered a large effort in the development of targeted therapies to treat these tumors. However, to date only a modest clinical benefit, limited to subsets of patients, has been demonstrated. Furthermore, despite a high degree of target selectivity, the use of targeted therapies often has systemic toxicity. The reasons behind this limited clinical success are complex and include the intricacy of the signaling pathways in gliomas and the heterogeneity of the disease process, compounded by existing limitations in assessing the efficacy of these novel agents when conventional end points and clinical trial designs are utilized. However, despite these difficulties targeted therapies remain a very attractive avenue of treatment for malignant gliomas. Three basic approaches are needed to overcome the hurdles associated with targeted therapies: first, further development of genetic profiling techniques will help to better determine the genetic changes and molecular pathways involved in gliomas and will potentially allow the design of individualized therapies based on the genetic and molecular signature of each tumor. Second, there is a need for the development of better combination strategies (complementary targeted agents or targeted agents with chemotherapy drugs) directed towards disease heterogeneity. Third, we need to optimize the design of preclinical and clinical trials to obtain the maximum amount of information in the shortest period of time.