Tumor cells harbor tens to thousands of genetic and epigenetic alterations that disrupt cellular pathways, providing them with growth and survival advantages. However, these benefits come at a cost, with uncontrolled cell growth, defective apoptosis, sustained pathological angiogenesis, immune evasion, and a metastatic phenotype occurring at the expense of the antiviral response of the individual tumor cell. Oncolytic virotherapy is an emerging therapeutic strategy that uses replication-competent viruses to selectivity kill cancer cells by exploiting their impaired antiviral response. In this review, we outline our understanding of the alterations in signaling pathways that simultaneously contribute to the malignant phenotype and virus-mediated killing of cancer cells.