Oncolytic virus therapy has been used for more than 50 years capitalizing on the properties of viruses to selectively kill or deliver genes to tumor cells. Viruses target tumor cells because the cells are growing and provide the biochemical machinery to facilitate virus replication, and many have deregulated the control measures that would impede a virus. These conditions allow viruses that are usually benign or lacking accessory genes for growth in normal cells to become oncolytic with selectivity for growth and killing of tumor cells. Reovirus, paramyxoviruses, adenovirus lacking the E1a or E1b genes, or herpes simplex virus lacking the ICP34.5 or ribonucleotide reductase become smart bombs that can seek out, target, and selectively destroy tumor cells. Alternatively, these and other viruses can carry genetic payloads for enzymes or immunological proteins to mark tumor cells for killing by drugs or host responses.