Glioblastoma remains the most clinically challenging tumor of the CNS, as evidenced by the dismal change in overall survival over the past 50 years. However, recent advances in high-throughput screening techniques have given rise to a wealth of new information regarding the aberrant signaling pathways that drive the tumor phenotype. Two of these so-called 'oncopathways' are NF-κB and JAK/STAT. This review will describe the basic mechanisms of these pathways, explore the relevance of NF-κB and JAK/STAT signaling in glioblastoma, and look ahead to experimental compounds that will integrate our knowledge of these pathways into existing therapies. © 2010 Expert Reviews Ltd.