Over the last 60 years an eclectic collection of microbes has been tested in a variety of pre-clinical models as anti-cancer agents. At the forefront of this research are a number of virus-based platforms that have shown exciting activity in a variety of pre-clinical models and are collectively referred to as oncolytic viruses. Our true understanding of the potential and limitations of this therapeutic modality has been substantially advanced through clinical studies carried out over the last 25 years. Perhaps not surprising, as with all other cancer therapeutics, it has become clear that current oncolytic virus therapeutics on their own are unlikely to be effective in the majority of patients. The greatest therapeutic gains will therefore be made through thoughtful combination strategies built upon an understanding of cancer biology.