Recurrent or metastatic cancer in most cases remains an incurable disease, and thus alternative treatment strategies, such as oncolytic virotherapy, are of great interest for clinical application. Oncolytic adenoviruses (Ads) have many advantages as virotherapeutic agents and have been safely employed in the clinics. However, the efficacy of oncolytic Ads is insufficient to eradicate tumors and current clinical applications are restricted to local administration against primary tumors because of immunological obstacles and poor tumor-cell targeting. Thus, alternative viable approaches are needed to establish therapies based on oncolytic Ad that will eliminate both primary and metastatic cancers. To this end, rational design of oncolytic Ads that express immunostimulatory genes has been employed. Even when restricted to local viral delivery, these oncolytic Ad-based immunotherapeutics have been shown to exert systemic antitumor immunity and result in eradication of both primary and metastatic cancers. Moreover, oncolytic Ad-based immunotherapeutics in combination with either dendritic cell-based vaccine or radiotherapy further strengthen the systemic tumor-specific immunity, resulting in complete suppression of both local and distant tumor metastatic growth. This review will focus on the most recent updates in strategies to develop potent oncolytic Ad-based immunotherapeutics for use in cancer gene therapy.