Glioblastoma multiforme (GBM) is an extremely aggressive tumor with a very dismal prognosis. Although extensive efforts have been made to identify new treatment options for these patients to improve their quality of life and survival, the results are not encouraging. The patients are left in a grim situation with a short life expectancy. During the past decade, several groups have demonstrated that human cytomegalovirus (HCMV) nucleic acids and proteins can be detected in GBM tumors, while healthy brain surrounding the tumors remains negative for this virus. While a currently ongoing debate argues for or against the presence of HCMV in GBM, DC vaccinations with GBM tumor lysates have been shown to trigger an HCMV-specific immune response in patients. Moreover, HCMVspecific autologous T cells have proven capable of killing GBM cells. These observations provide immunological evidence that HCMV epitopes exist in these tumors, and support the efforts to utilize HCMV as a target for immunotherapy in GBM patients. Indeed, several HCMV-based immunotherapy trials are ongoing with encouraging results for this group of patients. Furthermore, a retrospective analysis of a cohort of GBM patients who received the anti-HCMV drug Valganciclovir as add-on to standard therapy reveals a potential substantial increase in survival. Thus, we argue that the emerging possibilities to target HCMV to substantially improve the outcome of GBM patients should be given urgent attention. In this review, we discuss potential strategies for medical or immune-based therapies to target HCMV in the context of GBM.