Greater than 40% of glioblastomas (GBM) harbor focal amplification of the EGFR locus and there is evidence to suggest that these are driver alterations in these patients, making the EGFR pathway a potential therapeutic target in some clinical settings. Moreover, this alteration is relatively specific for GBM with very few other diffusely infiltrative gliomas having been shown to carry focal amplification of this locus (<3%). In GBM, this alteration frequently occurs in combination with other alterations of EGFR including polysomy 7, intragenic inframe deletions (e.g. EGFRvIII), and/or somatic point mutations. Based on current evidence, the independent predictive value of EGFR amplification in GBM is unclear. The relationship between individual and concurrent EGFR alterations and clinical response to small molecular inhibitors targeting EGFR is currently under investigation in clinical trials.