Since the early 2000s, high-risk E. coli clones that presented a highly virulent and multidrug resistance profile have been identified, and their genome is completely sequenced. Molecular techniques make it possible to follow the evolution and spread of those clones in different parts of the world. The results of several studies monitoring the emergence of new high-risk E. coli clones showed an increase in the number of clones and the virulence strategies and in the emergence of clones with the ability to cause intestinal and urinary infections combined with a multidrug resistance profile. We certainly can't stop the emergence of new high-risk clones. The remaining questions are: How can we use the knowledge about E. coli high-risk clones to our advantage in the war against multidrug antibiotic resistance? How can we stop the spread of those clones and improve diagnostic and treatment stewardship? This is a challenge that requires collaboration and shared knowledge.