Overview: Glioblastoma (GBM) is a highly malignant, rapidly progressive astrocytoma that is distinguished pathologically from lower-grade tumors by necrosis and microvascular hyperplasia. The global pattern of growth changes dramatically with the development of GBM histology and is characterized by hypoxia-driven peripheral expansion from a growing necrotic core. Necrotic foci present centrally in GBM and are typically surrounded by “pseudopalisading” cells—a configuration that is relatively unique and long recognized as an ominous prognostic feature. Theses pseudopalisades are severely hypoxic, overexpress hypoxia inducible factor-1 (HIF-1), and secrete proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8). The microvascular hyperplasia that emerges in response promotes peripheral tumor expansion. Recent evidence suggests that pseudopalisades represent a wave of tumor cells actively migrating away from central hypoxia that arises following a vascular insult. Vaso-occlusive and prothrombotic mechanisms in GBM could readily explain the presence of pseudopalisading necrosis in tissue sections, the rapid peripheral expansion on neuroimaging, and the dramatic shift to an accelerated rate of clinical progression as a result of hypoxia-induced angiogenesis. The genetic alterations that coincide with progression to GBM include amplification of epidermal growth factor receptor (EGFR), deletion of CDKN2A, and mutation or deletion of PTEN. Other diagnostic and prognostic tests used in neuro-oncology include assessment of 1p/19q, MGMT promoter methylation, IDH1, and p53. More recently, the Cancer Genome Atlas data have indicated that there are four robust transcriptional classes of GBM, referred to as proneural, neural, classical, and mesenchymal. These classes have genetic associations and may pave the road for future development of targeted therapies.