Spread to the central nervous system (CNS) and the leptomeninges is a frequent complication of systemic cancers that is associated with serious morbidity and high mortality. We have developed a novel therapeutic approach against primary CNS tumors and secondary CNS malignancy complicating systemic cancer based on the human neuropathogen poliovirus. Susceptibility to poliovirus infection and ensuing rapid cell lysis are mediated by the cellular poliovirus receptor CD155, as well as cell-internal factors involved in control of viral gene expression and genome replication. We observed that CD155, a putative cell adhesion molecule of the immunoglobulin superfamily physiologically expressed in the developing CNS, is ectopically expressed on numerous primary and secondary CNS neoplasms. An association with malignant cells renders CD155 a molecular target for therapeutic intervention with poliovirus. However, any therapeutic application of poliovirus must contend with its inherent neuropathogenic potential. Poliovirus gene expression is driven by the viral internal ribosomal entry site (IRES), which mediates translation initiation in a 5- end, cap-independent manner. We discovered that IRES function is subject to potent cell type-specific restrictions that can be exploited to selectively drive viral gene expression and propagation in cancerous cells. Polioviruses replicating under control of a heterologous IRES derived from their relative human rhinovirus type 2, displayed rapid growth and cell killing in cancerous cells. However, these recombinants failed to efficiently translate their genome and propagate in cells of neuronal lineage. Consequently, polio-/rhinovirus recombinants are non-pathogenic after intraspinal inoculation into mice transgenic for the poliovirus receptor CD155 and in non-human primates. Oncolytic poliovirus recombinants have shown promise in preclinical investigations against primary tumor explant cultures and in xenograft animal studies and are currently being prepared for phase-I clinical trials against glioblastoma multiforme.