ADENOVIRUSES WERE FIRST DISCOVERED half a century ago by Rowe and colleagues, who were trying to culture adenoid tissue in the laboratory (Rowe et al., 1953). Since that time, nonhuman adenoviruses have been isolated from a number of species including chimpanzees, pig, mouse, and dog, as well as other mammalian and avian species (Shenk, 1996). Although human adenoviruses cause significant levels of respiratory, ocular, and gastrointestinal disease, they have been the object of intense study over the years mainly as a model system for basic eukaryotic cellular processes such as transcription, RNA processing, DNA replication, translation, and oncogenesis. Early on, it was shown that the virus could recombine during growth in culture (Lewis et al., 1966a, b; Pierce et al., 1968; Lewis and Rowe, 1970), ultimately setting the stage for the use of the virus as a vector for gene delivery into cells, animals, and humans. Many features of adenovirus make it well suited for gene delivery, including the ability to grow recombinant viruses to high titers, a relatively high capacity for transgene insertion, and efficient transduction of both quiescent and actively dividing cells, usually without incorporation of viral DNA into the host cell genome. These characteristics, as well as the development of many methods for manipulating the viral genome, have made adenovirus a popular choice as a gene delivery vehicle. This is evidenced by the fact that adenovirus is currently being used in roughly one-quarter of all gene therapy clinical trials, making it second only to the use of retroviral vectors (Journal of Genetic Medicine Website, www. wiley. co. uk/genmed/clinical). In this review, we summarize our current understanding of the life cycle of the human adenoviruses and then discuss how the structure and function of viral genes impact the use of the virus as a gene delivery vehicle. Readers desiring a more comprehensive coverage of the biology of the virus are directed to the volumes edited by Doerfler and Böhm (2003, 2004).