PVS-RIPO is a genetically recombinant, non-pathogenic poliovirus chimera with a tumor-specific conditional replication phenotype. Consisting of the genome of the live attenuated poliovirus type 1 (Sabin) vaccine with its cognate IRES element replaced with that of human rhinovirus type 2, PVS-RIPO displays an inability to translate its genome in untransformed neuronal cells, but effectively does so in cells originating from primary tumors in the central nervous system or other cancers. Hence, PVS-RIPO unleashes potent cytotoxic effects on infected cancer cells and produces sustained anti-tumoral responses in animal tumor models. PVS-RIPO presents a novel approach to the treatment of patients with glioblastoma multiforme, based on conditions favoring an unconventional viral translation initiation mechanism in cancerous cells. In this review we summarize advances in the understanding of major molecular determinants of PVS-RIPO oncolytic efficacy and safety and discuss their implications for upcoming clinical investigations.