© 2008 by Taylor & Francis Group, LLC. The comparative genomics of viruses is a broad topic, in part because of the great variation in viral genome structures and associated replication strategies. This chapter, however, tries to focus on the value of comparative methods in the hope that it will be generally applicable. Since the volume of genomics data is ever increasing, we also emphasize the importance of bioinformatics tools in managing and analyzing genomic data in an efficient manner. For examples, we have drawn on our background with the Viral Bioinformatics Resource Center (VBRC; www.vbrc.org).