After a century of volatile interest in treating tumors with viruses, adenovirus has been used increasingly for the past century to treat cancer patients. Technical innovations have led to the production of safer oncolytic viruses, which can also be armed to make them more potent. In this chapter, ways of making the treatments more effective are described. Currently, it seems that oncolysis alone is not able to cure advanced cancers due to intratumoral complexities, and thus utilization of the immunogenic effects of oncolysis for activating anticancer immunity seems useful. Highlighting the need for rapid bench-to-bedside-and-back translation, oncolytic virus treatments are complex, especially when combined with standard chemotherapy, and thus the optimal scheduling is not yet known. One approach to allow patients access to oncolytic virus therapies was the Advanced Therapy Access Program, operational between 2007 and 2011, whose lessons are now being implemented in standard clinical trials. Eventually, randomized blinded trials are needed to confirm efficacy, and several of them are ongoing with different oncolytic viruses.