Standard treatment with temozolomide and radiotherapy for patients with newly diagnosed glioblastoma has increased the median overall survival and, more importantly, the 2-year survival rate of patients. However, as yet, no investigations have been conducted to define effective strategies against recurrence, which occurs in most patients following combined radiotherapy/temozolomide treatment. Furthermore, in recent years, new issues have emerged regarding the evaluation of disease response, and also with the identification of patterns such as pseudoprogression, frequently indistinguishable from real disease progression. New therapeutic strategies, such as targeted therapies and anti-angiogenic treatments that appear promising with regard to improving the results at the time of recurrence are discussed.