Oncolytic virotherapy exploits live viruses with selective tropism for cancerous cells and tissues to treat cancer. As discussed here, the field has progressed considerably as a result of both the successes and failures of previous and on-going clinical trials for various cancers. These studies indicate that oncolytic viruses are remarkably safe and more efficacious when virus replication stimulates sustained antitumor immune responses. In the future, virotherapy should be combined with immunomodulatory reagents that target immune tolerance to established cancers.