Escherichia coli has a complex and versatile nature and continuously evolves from non-virulent isolates to highly pathogenic strains causing severe diseases and outbreaks. Broadly protective vaccines against pathogenic E. coli are not available and the rising in both, multi-drug resistant and hypervirulent isolates, raise concern for healthcare and require continuous efforts in epidemiologic surveillance and disease monitoring. The evolving knowledge on E. coli pathogenesis mechanisms and on the mediated immune response following infection or vaccination, together with advances in the "omics" technologies, is opening new perspectives toward the design and development of effective and innovative E. coli vaccines.