The receptor for epidermal growth factor (EGFR) is a prime target for cancer therapy across a broad variety of tumor types. As it is a tyrosine kinase, small molecule tyrosine kinase inhibitors (TKIs) targeting signal transduction, as well as monoclonal antibodies against the EGFR, have been investigated as anti-tumor agents. However, despite the long-known enigmatic EGFR gene amplification and protein overexpression in glioblastoma, the most aggressive intrinsic human brain tumor, the potential of EGFR as a target for this tumor type has been unfulfilled. This review analyses the attempts to use TKIs and monoclonal antibodies against glioblastoma, with special consideration given to immunological approaches, the use of EGFR as a docking molecule for conjugates with toxins, T-cells, oncolytic viruses, exosomes and nanoparticles. Drug delivery issues associated with therapies for intracerebral diseases, with specific emphasis on convection enhanced delivery, are also discussed.