E. coli is a diverse bacterial species encompassing commensal as well as intestinal and extraintestinal pathogenic strains. The ability to adapt to so many different niches in the host organism is determined by the extreme genomic plasticity of E. coli. The genetic diversity is due to a complex phylogenetic structure in which besides the well-known main groups A, B1, B2 and D, four new groups, C, E, F and Clad I, have been characterized recently. The mobile gene pool exchanged by horizontal gene transfer (HGT) is another important driving force in the evolution of E. coli. Pathogenicity of strains is conditioned by a specific repertoire of virulence factors located on the mobile genetic elements and transmitted by HGT. The environment changing constantly stimulates the formation of new virulence gene combinations that generate the formation, not observed so far, of new pathogenic clones of higher capacity for virulence and greater expansiveness. The presence of very similar virulence plasmids carrying conserved combinations of the virulence genes (CVP) among extraintestinal pathogenic strains in humans and birds has been observed. It indicates a real possibility of occurrence of common virulence factors. The increase in drug resistance among pathogenic E. coli is also reflected in the prevalence of highly expansive clones exhibiting both high virulence and resistance. The presented data indicate that further studies are required to determine the interdependencies of resistance and virulence at the genetic level to help improve our management of the infectious diseases caused by these bacteria.