Progress in improving the prognosis of patients with glioblastoma has been modest and has predominantly relied on informative imaging, optimization of medical and surgical treatment, and approval of new drugs with modest benefits on overall and/or progression-free survival. This has frustrated clinicians and demoralized patients but has underscored the importance of pursuing novel treatment strategies in hopes of mounting a decisive assault on this disease. Although initially not intuitive, the use of a pathogen to treat cancer has become a radical and sophisticated strategy to combat the aggressive phenotype of this disease. In fact, the engineering of viruses to fight cancer is a field that has now reached scientific maturity and has rapidly progressed from preclinical stages to clinical testing with considerable safety but disappointing efficacy. Here we review the milestones of this therapy focusing on landmark clinical trials, shed light on the limitations of this approach, and describe the recent and future strategies aimed at bringing promising efficacy to this mode of therapy.