Glioblastoma multiforme (GBM) is the most common primary tumour of the central nervous system. The outcome after standard therapy, consisting of resection, radiation and chemotherapy, is poor: median survival is 40 to 60 weeks, with the tumour often recurring only a few millimetres away from the original location after gross total resection. The epidermal growth factor receptor (EGFR) is amplified and overexpressed in 40% to 50% of GBM, almost half of which co-expresses the mutated, constitutively activated EGFR variant III (EGFRvIII). As EGFR activation leads to cell proliferation, angiogenesis and reduced apoptosis, its increased activity may contribute to the aggressiveness of GBM. Therefore, to control these carcinogenic functions through EGFR inhibition is a logical therapeutic approach. Various trials of EGFR antagonists are ongoing, investigating tyrosine kinase inhibitors (TKIs), monoclonal antibodies (MAbs), RNA-based agents and vaccination against EGFRvIII. While TKIs, e.g. erlotinib and gefitinib, are currently the most advanced in clinical development, numerous trials indicate that a multiple target approach might be necessary to achieve therapeutically relevant effects.