Streptococcus pneumoniae is the most common cause of bacterial illness worldwide, causing more than 1.5 million deaths per year. We recently characterized a randomly switching DNA methyltransferase, the SpnD39III system, that regulates multiple genes in a system called a phasevarion (phase-variable regulon). All previously reported phasevarions regulate genes that mediate immune-evasion and play a key role in virulence. The SpnD39III system shuffles between six different DNA methyltransferase specificities, each of which regulates a different phasevarion, meaning a pneumococcal population contains six phenotypically distinct sub-populations. We have demonstrated that particular allelic variants of the SpnD39III system are selected for in particular host niches using a mouse model of infection: the SpnD39III-A allele is selected for in blood just 4 hours post challenge, whereas no net phase-variation occurs over a seven day period in a nasopharyngeal colonization model. Biofilm formation, antibiotic resistance, and protein vaccine candidate expression are all influenced by SpnD39III phase-variation, meaning this system has a central role in pneumococcal virulence. Examination of the related organism S. suis, an important pig pathogen, and a major cause of bacterial meningitis in humans, reveals this organism contains multiple phase-variable methyltransferases. A distinct system clusters with a particularly virulent zoonotic clade, and the role of each particular phasevarion is currently being characterized. Examination of the restriction-modification database REBASE shows that approximately 30% of all DNA methyltransferases are phase-variable, and that this is a common contingency strategy for a wide range of bacterial species, from host-adapted pathogens to environmental organisms. Characterizing phasevarions is critical to understanding bacterial pathobiology, and to vaccine design; it is not possible to define the stably expressed antigenic repertoire of any organism containing phase-variable DNA methyltransferases without first defining the gene expression changes resulting from phasevarion switching.