Virotherapy is the use of oncolytic or tumor-selective viruses to treat cancer. The replication of the virus inside a tumor can debulk the tumor mass and simultaneously, revert the immune suppressor environment that causes the immune escape of tumor cells. This therapeutic approach was discovered ten years ago but it has been renewed in the last decade with designed viruses. Adenovirus (Ad) is a nonenveloped DNA virus that infects broadly tumor cells and it has been frequently used in cancer gene therapy and virotherapy. A very high level of tumor-specific replication has been obtained with adenoviruses by replacing early viral gene promoters with tumorselective promoters. However, the complex Ad capsid interactions with blood proteins and cells and, also with liver and spleen macrophages result in rapid blood clearance and the prevention of systemic tumor targeting. To settle these problems, a new field is emerging where an oncolytic Ad genome is complexed to non-viral vectors to target tumors.