Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Especially in this disease, qualitative and quantitative aspects render the dysregulated epidermal growth factor receptor (HER1/EGFR) an outstanding therapeutic target. A variety of therapeutic compounds was developed to target HER1/EGFR among which the clinically most advanced agents are small molecule tyrosine kinase (TK) inhibitors. Unfortunately, clinical studies examining their therapeutic efficacy have so far failed to document a major therapeutic break-through in the setting of GBM. Thus, the targeted approach against HER1/EGFR likely requires a synergistic drug combination strategy to ultimately become successful in this disease. This patents review focuses on innovative therapeutic strategies combining HER1/EGFR-targeted TK inhibitors with novel agents which for the most part have not been evaluated for the treatment of GBM yet but which constitute interesting candidates for further evaluation in this setting.