Clinical isolates of carbapenem-resistant Klebsiella pneumoniae that belong to multilocus sequence type 258 (ST258) have emerged as important nosocomial pathogens, and it has been proposed that all of these isolates are derived from a single genetic clone that has spread globally. However, genome sequencing and phylogenetic analysis of 83 ST258 clinical isolates from a range of geographical locations now reveals that there are two distinct genetic clades, which disproves the single-clone hypothesis. DeLeo et al. identified a ∼215 kb region that accounts for most of the genetic divergence between the clades, which also seems to be a hot spot for recombination. Thus, the authors suggest that the genetic plasticity associated with this recombination hot spot — which includes the genes involved in the synthesis of the polysaccharide capsule (a major contributor to immune evasion) — might underlie the global success of ST258 isolates as human pathogens.