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The current standard care of treatment for glioblastoma multiforme (GBM) is never curative and exclusively involves the use of cytoxics upfront (e.g., radiation and chemotherapy). Current clinical protocols involve the use of single-agent targeted therapies, which inhibit specific pathways. Given the functional redundancies present in human tumors and escape mechanisms, it is highly unlikely that such a monotherapy approach will be successful in the treatment of GBM. Future directions of therapy for GBMs will likely involve the use of therapeutic cocktails, including more than one target specific inhibitors based on tumor escape mechanism, genetic, epigenetic and molecular signatures. This review addresses some of the relevant issues.Correlative clinical studies from various clinical trials and preclinical studies have provided the meticulous use of chemotherapeutics and radiation based on molecular profiling of tumors. Alkylating agents such as temozolomide lose their efficacy if DNA repair enzyme expression is upregulated. The alternative strategies include targeting the enzyme or one can use poly (ADP) ribose inhibitor to inhibit base excision repair pathway rather than mismatch repair pathway. Currently, several inhibitors in this category are in clinical trials. Next, we have addressed new avenues including radiosensitizers, hypoxia, metabolism, angiogenesis, invasive and infiltrative nature of tumors and potential molecular targets, which can be exploited for clinical trials. Finally, we have included some aspect of genome-wide association studies and correlative analysis and the lessons learned to design better clinical trials.Advances in profiling the noncoding RNAs, genetic, epigenetic profiles, metabolomics, genomics and proteomics may uncover important resistance mechanisms in GBM. Personalized therapy using various therapeutic cocktails targeting these resistance mechanisms may prove even more effective in the future management of GBMs.