Activated epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target for a variety of solid tumors, particularly malignant gliomas. Mutation or amplification of EGFR is commonly observed in malignant gliomas and these modifications are associated with increased cell proliferation and radiation resistance. Small-molecule kinase inhibitors targeting the intracellular kinase domain of the EGFR and monoclonal antibodies against the extracellular domain of the EGFR have demonstrated in vitro efficacy and have spawned clinical trials incorporating EGFR inhibition into the management of malignant gliomas, for example, combining EGFR inhibitors with radiation therapy. This early clinical experience indicates that EGFR inhibitors are well tolerated; however, it remains unclear how best to integrate EGFR inhibition into the management of malignant gliomas. As signaling pathways become better defined, patients may be treated with EGFR inhibitors based on the molecular features of their tumors and treatment efficacy may be improved by combining EGFR inhibition with other small kinase inhibitors and radiation therapy.