The alteration of the epidermal growth factor receptor (EGFR)-driven signaling network is a characteristic feature of glioblastomas (GBM), and its inhibition represents a treatment strategy. However, EGFR-targeted interventions have been largely ineffective. Complex perturbations in this system are likely to be central to tumor cells with high adaptive capacity and resistance to therapies. We review key concepts and mechanisms relevant to EGFR-targeted treatment resistance at a systems level. Our understanding of treatment resistance as a systems-level phenomenon is necessary to develop effective therapeutic options for GBM patients. This is allowing us to go beyond the notion of therapeutic targets as single molecular components, into strategies that can weaken cancer signaling robustness and boost inherent network-level vulnerabilities.