Glioblastoma is the most common and most fatal primary malignant brain tumor in adults. Despite progress in characterizing the genetic and molecular mechanisms of glioblastomas, advances in treatment that translate into substantial improvement in prognosis have yet to be realized. A role for cytomegalovirus in glioblastoma pathogenesis was proposed more than a decade ago and has generated considerable debate as a possible therapeutic target. Independent groups have had variable success in detecting cytomegalovirus infection in tumor cells; the overall consensus is that very low levels of viral proteins and nucleic acids can be observed. Although cytomegalovirus has not been found to be oncogenic in this context, a possible oncomodulatory role has been suggested. A recent clinical trial evaluating valganciclovir as an adjuvant therapy for the treatment of glioblastoma did not demonstrate a beneficial effect on tumor growth or overall survival, although retrospective analysis subsequently indicted a significant survival benefit. In light of the publicity of that report, patients and neuro-oncologists are requesting cytomegalovirus testing to justify antiviral treatment. Based on questions on the significance of cytomegalovirus infection in glioblastomas and the lack of a clear clinical benefit of valganciclovir, we reviewed this topic and conclude that, at this time, there is insufficient evidence to recommend routine testing and treatment.