Recent data has shown that viruses such as vesicular stomatitis virus (VSV), a relatively non-pathogenic, negative-stranded RNA virus, can preferentially replicate in malignant cells and less so in normal cells. VSV appears able to carry out this function in transformed cells since these hosts exhibit the hallmarks of flawed host defense, probably involving the interferon system, which is essential for preventing virus replication. The simple genetic constitution of VSV, lack of any known transforming, integrating or reassortment properties, extensive knowledge relating to its interaction with the immune system and the ability to genetically manipulate this agent affords an ideal opportunity to exploit the oncolytic and gene targeting potential of this innocuous virus. Thus, aside from preferentially targeting malignant cells VSV recombinants could be generated that could increase a tumor's susceptibility to chemotherapeutic agents and/ or importantly, the host immune response. Collectively, our data and others demonstrate that VSV as well as other RNA viruses could provide a promising and exciting approach to cancer therapy.