Multilocus sequence typing reveals that many bacterial species have a clonal structure and that some clones are widespread. This underlying phylogeny was not revealed by pulsed-field gel electrophoresis, a method better suited to short-term outbreak investigation. Some global clones are multiresistant and it is easy to assume that these have disseminated from single foci. Such conclusions need caution, however, unless there is a clear epidemiological trail, as with KPC carbapenemase-positive Klebsiella pneumoniae ST258 from Greece to northwest Europe. Elsewhere, established clones may have repeatedly and independently acquired resistance. Thus, the global ST131 Escherichia coli clone most often has CTX-M-15 extended-spectrum β-lactamase (ESBL), but also occurs without ESBLs and as a host of many other ESBL types. We explore this interaction of clone and resistance for E. coli, K. pneumoniae, Acinetobacter baumannii– a species where three global lineages dominate – and Pseudomonas aeruginosa, which shows clonal diversity, but includes the relatively ‘tight’ serotype O12/Burst Group 4 cluster that has proved adept at acquiring resistances – from PSE-1 to VIM-1 β-lactamases – for over 20 years. In summary, ‘high-risk clones’ play a major role in the spread of resistance, with the risk lying in their tenacity – deriving from poorly understood survival traits – and a flexible ability to accumulate and switch resistance, rather than to constant resistance batteries.