Transmission of antibiotic resistance genes may be mediated by a variety of molecular mechanisms, from mobility of small genetic elements to clonal spread. Since 1997, the carbapenem-hydrolyzing enzyme Klebsiella pneumoniae carbapenemase (KPC) has spread in the United States and across the world, mainly via a single K. pneumoniae clone, sequence type 258. By tracking the trail of dissemination of the bla(KPC) gene inside their institution, Mathers et al. (mBio 2:e00204-11, 2011) have shown evidence of the ability of this gene to spread by several modes, including plasmid transfer and clonal spread. The ever-evolving modes of transmission of resistance genes challenge our ability to detect, track, and eventually control the spread of what has become a major threat to hospitalized patients worldwide.