The management of recurrent high-grade gliomas with conventional, as well as targeted, therapies is problematic owing to several confounding issues. First, the diagnosis of recurrence using MRI is not straightforward, making the assessment of images in daily routines, as well as in clinical trials, challenging. While chemotherapies with cytotoxic agents have demonstrated initial treatment response, most tumors recur quickly. Second, targeted therapy itself is confounded by the heterogeneous expression of drug targets and nonlinear signaling effects, with functional redundancy and sidestream feedback mechanisms resulting in treatment failure; however, several active agents have been identified, most notably, bevacizumab (an antibody that sequesters VEGF), cilengitide (an inhibitor of integrin αvβ3/5 signaling) and cediranib (an oral tyrosine kinase inhibitor targeting PDGF receptor, c-Kit and all VEGF receptor subtypes). All of these agents have undergone multiple clinical trials and have demonstrated benefits and progression-free survival prolongation in recurrent disease. Given these advances, it is likely that tailored therapies for tumors harboring specific signaling defects will become more efficient and successful in the management of glioblastoma.