E. coli was one of the first bacteria to have the complete genome decoded and these organisms have been the focus of genomic studies for approximately the last 15 years. While early studies suggested the diversity of the species may be limited, the generation of multiple genomes rapidly identified significant genomic diversity. Whole genome sequence analysis has demonstrated significant genetic variability even within each pathovar. Furthermore, next generation sequencing has identified the distribution of genes across the E. coli species and provided insights into the evolution of the species. In the coming years, decreased sequencing costs are likely to positively affect the understanding of pathogenesis in this important human pathogen.