Glioblastoma is the most common and aggressive form of brain tumor in adults and has a poor prognosis and a high recurrence rate despite optimal care. The management of patients with relapsed glioblastoma is challenging, with no widely agreed standard of care. Different chemotherapy and radiotherapy combination treatment strategies provide only modest benefits. Recently, several novel agents, including bevacizumab and XL-184, have demonstrated promising results in Phase II trials with their further evaluation ongoing in Phase III randomized trials. Interpreting the data from such trials is a key challenge in glioblastoma, highlighting the need for relevant and standardized patient assessment techniques. Data from ongoing and planned trials should help to define optimal treatment strategies for this disease.