Despite slow clinical progress, efforts to develop specific nontoxic cancer gene therapies are increasing exponentially. Adenoviral vectors are one of the most popular vehicles for gene transfer currently being used in worldwide clinical trials for cancer. Over the past decade our knowledge of the adenoviral life cycle together with the discovery of novel tumor antigens has permitted the targeting of adenoviral vectors to specific tumors. Targeting adenoviral vectors to tumors is crucial for their use in clinical applications in order to allow for systemic administration and the use of reduced vector doses. In addition, novel approaches to tumor killing have also been explored, which will have greater potency and selectivity than currently available treatments such as chemotherapy or radiation. This review discusses the basic concepts behind the use of adenoviral vectors for cancer gene therapy and their potential for clinical application, as well as ongoing and completed clinical trials.