R-M systems are major players in the co-evolutionary interaction between mobile genetic elements (MGEs) and their hosts. Genes encoding R-M systems have been reported to move between prokaryotic genomes within MGEs such as plasmids, prophages, insertion sequences/transposons, integrative conjugative elements (ICEs) and integrons. However, it was recently found that there are relatively few R-M systems in plasmids, some in prophages, and practically none in phages. On the other hand, all these MGEs encode a large number of solitary R-M genes, notably MTases. In light of this, it is likely that R-M mobility may be less dependent on MGEs and more dependent, for example, on the existence of small genomic integration hotspots. It is also possible that R-M systems frequently exploit other mechanisms such as natural transformation, vesicles, nanotubes, gene transfer agents or generalized transduction in order to move between genomes.