Activation of NF-kappaB affects multiple aspects of cancer biology including cell survival and resistance to treatment. Glioblastoma (GBM) is the most common primary malignant tumor of the brain in adults and is resistant to treatment. Recent studies have reported that NF-kappaB activation in GBM is widespread and have elucidated the underlying regulatory mechanisms. EGFR gene amplification and mutation are among the key genetic alterations in GBM, and aberrant EGFR signaling is a key activator of NF-kappaB in GBM. In this review we discuss the evidence for activation of NF-kappaB in GBM and the key signaling pathways involved. Substantial evidence suggests a role for NF-kappaB in the pathogenesis of GBM and its resistance to treatment, indicating that NF-kappaB pathways may be useful targets for treatment.