Pathogenic Escherichia coli strains cause a wide variety of intestinal and extraintestinal infections. The widespread geographical clonal dissemination of intestinal pathogenic E. coli strains, such as E. coli O157:H7, is well recognized, and its spread is most often attributed to contaminated food products. On the other hand, the clonal dissemination of extraintestinal pathogenic E. coli (ExPEC) strains is also recognized, but the mechanism of their spread is not well explained. Here, I describe major pandemic clonal lineages of ExPEC based on multilocus sequence typing (MLST), and discuss possible reasons for their global dissemination. These lineages include sequence type (ST)131, ST393, ST69, ST95, and ST73, which are all associated with both community-onset and healthcare-associated infections, in particular urinary tract infections and bloodstream infections. As with many other types of drug-resistant Gram-negative and Gram-positive bacterial infections, drug-resistant ExPEC infections are recognized to be caused by a limited set of clonal lineages. However, reported observations on these major pandemic lineages suggest that the resistance phenotype is not necessarily the determinant of their clonal dissemination. Both epidemiological factors and their intrinsic biological 'fitness' are likely to contribute. An important public health and clinical concern is that pandemicity itself may be a determinant of progressive drug resistance acquisition by clonal lineages. New research is urgently needed to better understand the epidemiological and biological causes of ExPEC pandemicity.