The continuing and rapid increase in the number of fully sequenced genomes is creating new opportunities for comparative studies. However, although many genomic databases store data from multiple organisms, for the most part they provide limited support for comparative genomics. We argue that refocusing genomic data management to provide more direct support for comparative studies enables systematic identification of important relationships between species, thereby increasing the value that can be obtained from sequenced genomes. The principal result of the paper is a methodology, in which comparative analyses are constructed over a foundation based on sequence clusters and evolutionary relationships. This methodology has been applied in a systematic study of the fungi, and we describe how comparative analyses have been implemented as an analysis library over the e-Fungi data warehouse.