This article examines the role of genomics in the understanding and identification of O157:H7 enterohemorrhagic Escherichia coli (EHEC). We highlight the development of novel molecular typing systems that are based on the genomic sequence that has been generated for this pathotype. The genomic comparisons of EHEC to other E. coli strains highlight the close relatedness of the O157 and O55 isolates and also identify other non-O157 clades of isolates that appear to have a different genomic history. Analysis within the EHEC isolates must be completed on a fine scale using whole-genome sequence-based approaches to assess both the conserved and lateral acquired gene content. The plethora of genomic data for EHEC isolates has provided the ability to examine this pathotype in detail, which has provided opportunities for novel surveillance, detection, and diagnostics.