Key challenges facing cancer therapy are the development of tumor-specific drugs and the implementation of potent multimodal treatment regimens. Oncolytic adenoviruses, featuring cancer-selective viral cell lysis and spread, constitute a particularly interesting drug platform towards both goals. First, as complex biological agents, adenoviruses allow for rational drug development by genetic incorporation of targeting mechanisms that exert their function at different stages of the viral replication cycle. Secondly, therapeutic genes implementing diverse cancer cell-killing activities can be inserted into the oncolytic adenovirus genome without loss of replication potential, thus deriving a "one-agent combination therapy". This article reviews an intriguing approach to derive oncolytic adenoviruses, which is to insert cellular genetic regulatory elements into adenovirus genomes for control of virus replication and therapeutic gene expression. This approach has been thoroughly investigated and optimized during the last decade for transcriptional targeting of adenovirus replication and gene expression to a wide panel of tumor types. More recently, further cellular regulatory mechanisms, such as mRNA stability and translation regulation, have been reported as tools for virus control. Consequently, oncolytic adenoviruses with a remarkable specificity profile for prostate cancer, gastrointestinal cancers, liver cancer, breast cancer, lung cancer, melanoma, and other cancers were derived. Such specificity profiles allow for the engineering of new generations of oncolytic adenoviruses with improved potency by enhancing viral cell binding and entry or by expressing therapeutic genes. Clearly, genetic engineering of viruses has great potential for the development of innovative antitumor drugs--towards targeted and multimodal cancer therapy.