Adenovirus provides an attractive candidate tool to destroy tumor cells. However, to fulfill the expectations, selective targeting of tumor cells is mandatory. This chapter reviews critical aspects in the design of tumor-targeted adenovirus vectors and oncolytic adenoviruses. The review focuses on genetic modifications of capsid and regulatory genes that can enhance the therapeutic index of these agents after systemic administration. Selectivity will be considered at different levels: biodistribution selectivity of the injected virus particles, transductional selectivity defined as cell receptor interactions and trafficking that lead to virus gene expression, transcriptional selectivity by means of tumor-selective promoters, and mutation-rescue selectivity to achieve selective replication. Proper assays to analyze selectivity at these different levels are discussed. Finally, mutations and transgenes that can enhance the potency and efficacy of tumor-targeted adenoviruses from virocentric or immunocentric points of view will be presented.