Whole genome sequencing has revolutionized biological sciences, and is leading to a paradigm shift in microbiology. As more microbial genomes are sequenced, and more bioinformatics tools are developed, it has become possible to predict the metabolism of an organism from genomic data. In contrast, predicting the pathogenic potential of parasitic microbes and their interactions with their hosts is still a challenge, especially as the definition of pathogenesis itself is still evolving. In this review, we introduce the subsystem-based technology for genome annotation and analysis, and we discuss some subsystem-based tools available in the National Microbial Pathogen Data Resource (NMPDR, http://www.nmpdr.org) and their potential application in comparative genomics and pathogenomics. Copyright © 2009 S. Karger AG, Basel.