The current field of oncolytic virus development has evolved from, and been educated by, the route adenoviruses have taken to Phase III development in the United States (Onyx-015) and commercial approval in China (H101). Clinical development of these E1B-deleted viruses showed that a staged approach, from single-agent intratumoral injections to trials testing intravenous delivery and trials in combination with approved therapies is judicious and can be successful. Additional oncolytic products are in development, including andenovirus plus other promising platforms such as herpes simplex virus, Newcastle disease virus, reovirus and vaccinia virus. These second-generation products seek to expand clinical utility beyond the modest local efficacy of Onyx-015/H101 to potent systemic delivery and efficacy. Improvement of efficacy in metastatic cancer will depend not only on enhanced killing of tumor cells, but also on achieving intravenous delivery and better intratumoral dissemination. Many viruses inherently replicate preferentially in tumors, and engineering can increase this therapeutic index by targeting genetic features of cancers. However, both viruses and cancer cells have complex biologies. Therefore, research may reveal that there is not a single predictive factor for tumor specificity. For example, the Onyx-015 mechanism-of-selectivity has proved to be complex. Further research regarding pathway dependence for other oncolytic viruses may also reveal multiple influences on their tumor tropism.