Oncolytic viruses possess several key attributes that make them a highly attractive treatment for cancer. They exhibit clinically validated synergy with chemotherapy and an ability to selectively destroy tumor cells to the exclusion of normal cells. Oncolytic viruses can replicate and, therefore, amplify their dose in a tumor-dependent manner. In addition, they can be genetically manipulated to include additional therapeutic factors to create a multimodal anticancer agent. These characteristics lead to the expectation that oncolytic viruses will serve as an additional tool in the treatment repertoire of clinical oncologists. In their clinical development to date, these agents were safe and well tolerated, but lacked efficacy as monotherapies. In this review, three genetic-based methods to increase the potency and efficacy of oncolytic viruses, in which human adenovirus is utilized as an example of a prototype oncolytic virus, are discussed.