During the last decade adenovirus has lost its appeal in gene therapy due to a high immunogenicity that leads to a transient gene expression. However, adenovirus has gained attention as replication-competent vector to treat cancer. Designed for virotherapy, adenovirus has been successfully modified to replicate selectively in tumor cells. After the initial clinical trials with tumor-selective adenoviruses, it has become clear that further improvements on tumor targeting, intratumoral dissemination, and modulation of antiviral and antitumor immune responses are needed to effectively treat cancer. The non-viral delivery of infectious DNA encoding an oncolytic adenovirus armed with extracellular matrix-degrading genes and with genes that regulate the immune system to favor antitumor instead of antiviral immunity are key in the design oncolytic adenovirus.