Epidermal growth factor receptor (EGFR) gene amplification and activating mutations are common findings in glioblastomas. EGFR is at the top of a downstream signaling cascade that regulates important characteristics of glioblastoma cells, including cellular proliferation, migration, and survival. Targeting EGFR has therefore been regarded as a promising therapeutic strategy in glioblastoma for decades. However, although various pharmacological inhibitors and anti-EGFR antibodies are available, the antiglioma activity of these agents has been largely limited to preclinical models, whereas their administration to glioblastoma patients was characterized by lack of clinical benefit. Comprehensive efforts have been made within the last years to understand the underlying mechanisms that confer resistance to EGFR inhibition in glioma cells. The absence of well-known mutations that predict response to EGFR tyrosine kinase inhibitors (TKIs) in gliomas as well as the presence of redundant and alternative compensatory pathways are among the most important escape mechanisms that prevent potent antiglioma effects of EGFR-targeting drugs. Accordingly, an increasing number of in vitro and in vivo studies are aimed at overcoming this resistance by combinatorial approaches using anti-EGFR treatment together with one or more additional drugs. Novel insights into the molecular mechanisms mediating resistance to anti-EGFR treatment and promising combinatorial approaches may help to better define a future role for EGFR inhibition in the treatment of glioblastoma.