The increasing prevalence of chronic and hospital-acquired infections produced by multidrug-resistant
(MDR) or extensively drug-resistant (XDR) Pseudomonas aeruginosa strains is associated with significant
morbidity and mortality. This growing threat results from the extraordinary capacity of this pathogen for
developing resistance through chromosomal mutations and from the increasing prevalence of trans-
ferable resistance determinants, particularly those encoding carbapenemases or extended-spectrum
-lactamases (ESBLs). P. aeruginosa has a nonclonal epidemic population structure, composed of a limited
number of widespread clones which are selected from a background of a large quantity of rare and unre-
lated genotypes that are recombining at high frequency. Indeed, recent concerning reports have provided
evidence of the existence of MDR/XDR global clones, denominated high-risk clones, disseminated in hos-
pitals worldwide; ST235, ST111, and ST175 are likely those more widespread. Noteworthy, the vast
majority of infections by MDR, and specially XDR, strains are produced by these and few other clones
worldwide. Moreover,the association of high-risk clones, particularly ST235, with transferable resistance
is overwhelming; nearly 100 different horizontally-acquired resistance elements and up to 39 different
acquired -lactamases have been reported so far among ST235 isolates. Likewise, MDR internationally-
disseminated epidemic strains, such as the Liverpool Epidemic Strain (LES, ST146), have been noted as
well among cystic fibrosis patients. Here we review the population structure, epidemiology, antimicrobial
resistance mechanisms and virulence of the P. aeruginosa high-risk clones. The phenotypic and genetic
factors potentially driving the success of high-risk clones, the aspects related to their detection in the
clinical microbiology laboratory and the implications for infection control and public health are also
discussed.