Angiogenesis is a key pathologic feature of glioblastoma, which is the most common and most lethal primary brain tumor in adults. The degree of angiogenesis has been shown to be inversely related to patient survival. However, the molecular changes leading to angiogenesis in glioblastoma remain poorly understood. In the present study, we found a direct correlation between nuclear factor (NF)-kappaB activation and angiogenesis in glioblastomas. Blockade of NF-kappaB signaling significantly inhibited glioblastoma growth and angiogenesis in nude mice. These effects were consistent with significant inhibition of the expression of multiple angiogenic molecules, including vascular endothelial growth factor, and interleukin-8, in vitro and in vivo. Furthermore, blockade of NF-kappaB signaling also significantly inhibited the angiogenic potential of glioblastoma cells in vitro and angiogenesis of brain tumors in mouse xenograft models. Collectively, these results suggest that NF-kappaB activation plays a critical role in the growth and progression of glioblastoma and is a potential target for therapy for human glioblastoma.