It has been 9 years since the beginning of the first clinical trial in which an oncolytic virus was administered to cancer patients. Since then, oncolytic viruses from five different species have been taken to phase I and II clinical trials in over 300 cancer patients. While additional studies will be required to ascertain if the efficacy of any of these agents is high enough to warrant adding them to the existing therapeutic regimen, it has been reassuring that DNA viruses engineered to achieve tumor selectivity and RNA viruses with relative inherent natural tumor selectivity have proven reasonably safe at the wide range of doses that were tested. Here, we review the biology and clinical results of these five species of viruses and discuss lessons learned and challenges for the future.