The use of microarray and comparative genomic technologies for the analysis of host-pathogen interactions has led to a greater understanding of the biological systems involved in infectious disease processes. Transcriptome analysis of intracellular pathogens at single or multiple time points during infection offers insight into the pathogen intracellular lifecycle. Host-pathogen transcriptome analysis in vivo, over time, enables characterization of both the pathogen and the host during the dynamic, multicellular host response. Comparative genomics using hybridization microarray-based comparative whole-genome resequencing or de novo whole-genome sequencing can identify the genetic factors responsible for pathogen evolutionary divergence, emergence, reemergence or the genetic basis for different pathogenic phenotypes. Together, microarray and comparative genomic technologies will continue to advance our understanding of pathogen evolution and assist in combating human infectious disease.