Extra-intestinal pathogenic Escherichia coli (ExPEC) have a complex phylogeny, broad virulence factor (VF) armament and significant genomic plasticity, and are associated with a spectrum of host infective syndromes ranging from simple urinary tract infection to life-threatening bacteraemia. Their importance as pathogens has come to the fore in recent years, particularly in the context of the global emergence of hyper-virulent and antibiotic resistant strains. Despite this, the mechanisms underlying ExPEC transmission dynamics and clonal selection remain poorly understood. Large-scale epidemiological and clinical studies are urgently required to ascertain the mechanisms underlying these processes to enable the development of novel evidence-based preventative and therapeutic strategies. In the current review, we provide a concise summary of the methods utilised for ExPEC phylogenetic delineation before exploring in detail the associations between ExPEC VFs and site-specific disease. We then consider the role of ExPEC as an intestinal colonist and outline known associations between ExPEC clonal variation, specific disease syndromes and antibiotic resistance.