The development of multidrug resistance in bacteria is a global public health concern, and the genetic and molecular determinants that enable multidrug resistance need to be resolved. It is notable, however, that multidrug resistance is not uniform across all strains of Escherichia coli and is instead concentrated in specific lineages, such as ST131. In an effort to understand this, Connor et al. have now shown that multidrug-resistant (MDR) E. coli ST131 have a selective advantage over commensal bacteria in colonizing the mouse gut. The authors used three strains of E. coli: a non-MDR ST73 commensal strain (822-E8) isolated from a healthy human volunteer; an extra-intestinal pathogenic (ExPEC) ST73 strain (F084) that is not MDR and was isolated from a patient with bacteremia; and a pathogenic MDR ExPEC ST131 strain (F016) isolated from a patient with bacteremia. Competitive colonization experiments were done with combinations of two strains introduced into germ-free mice via oral gavage. Both ExPEC strains outcompeted the commensal strain. Then, the commensal strain was allowed to establish colonization first, followed by introduction of the MDR strain by oral gavage or by co-housing with MDR-strain-colonized mice, which led to displacement of the commensal strain from the gut. Conversely, the commensal strain was unable to displace the MDR strain when the mice were colonized with the MDR strain first. A pan-genome analysis of the three strains revealed that MDR lineages of E. coli with a greater proportion of genes encoding molecules linked to antimicrobial resistance have more genes encoding molecules related to carbohydrate metabolism and transport. These results raise interesting questions about the underlying mechanisms by which diversification in carbohydrate metabolism confers multidrug resistance.