Rapid advances are being made in the engineering of replication-competent viruses to treat cancer. Adenovirus is a mildly pathogenic human virus that propagates prolifically in epithelial cells, the origin of most human cancers. While virologists have revealed many details about its molecular interactions with the cell, applied scientists have developed powerful technologies to genetically modify or regulate every viral protein. In tandem, the limited success of nonreplicative adenoviral vectors in cancer gene therapy has brought the old concept of adenovirus oncolysis back into the spotlight. Major efforts have been directed toward achieving selective replication by the deletion of viral functions dispensable in tumor cells or by the regulation of viral genes with tumor-specific promoters. However, the predicted replication selectivity has not been realized because of incomplete knowledge of the complex virus-cell interactions and the leakiness of cellular promoters in the viral genome. Capsid modifications are being developed to achieve tumor targeting and enhance infectivity. Cellular and viral functions that confer greater oncolytic potency are also being elucidated. Ultimately, the interplay of the virus with the immune system will likely dictate the success of this approach as a cancer therapy.