Phase variation, the high-frequency reversible switching of gene expression, is a common feature of host-adapted bacterial pathogens and is generally associated with genes encoding surface factors. However, in a growing number of host-adapted pathogens, phase variation also occurs in genes encoding methyltransferases associated with type III restriction–modification (R-M) systems. Phase variable mod genes have been shown to regulate global gene expression and virulence phenotypes in the pathogenic Neisseria, Haemophilus influenzae, and Helicobacter pylori. The wide distribution of these systems indicates that this is a common strategy used by host-adapted bacterial pathogens to randomly switch between distinct “differentiated” cell types.