Recent advances in DNA sequencing technology have made the whole-genome sequencing of pathogens in a clinically relevant turn-around time both technically and economically feasible. The DNA sequencing of pathogens with epidemic potential offers new and exciting opportunities for high-resolution public health surveillance. This chapter outlines major methods and bioinformatics tools for pathogen genome characterization, the identification of infectious disease clusters, as well as for genomics-guided biosurveillance. Existing challenges are also considered.