Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients. Despite multimodal treatment with maximal safe surgical resection followed by concurrent radiochemotherapy and adjuvant chemotherapy with temozolomide, the prognosis remains poor with a median survival of 1 year. The survival rate at 5 years is 5% and, theoretically, all glioblastomas relapse [1]. Once tumors progress, treatment options are limited, and the management of recurrent glioblastoma remains challenging. The standard of care for second-line treatment has not been defined; options include surgery, re-irradiation, systemic pharmacotherapy, and, in Europe, mostly lomustine [2,3]. The general and neurological health status of the patient, the molecular findings, the time to first recurrence, the pattern of recurrence, and previous treatment have to be considered. Nitrosoureas or temozolomide rechallenge show limited efficacy. Anti-vascular endothelial growth factor (VEGF) bevacizumab prolonged progression-free survival (PFS), but did not improve overall survival (OS) [4]. Because the treatment of recurrent glioblastoma remains a highly unmet clinical need, deeper mechanistic insight into the molecular changes present in these tumors is required. The enrollment of recurrent glioblastoma patients in clinical trials investigating new therapeutic options should be considered carefully whenever possible. In this Special Issue, we present some of the exciting updates on recurrent glioblastomas, which may help shape future treatment options.