Many bacterial pathogens encode randomly-switching methyltransferases that control phase-variable regulons – phasevarions. All phasevarions characterised to-date control expression of genes involved in pathogenesis and host-adaptation, and many regulate putative and current vaccine candidates. Effective vaccines require stably expressed targets: individual phase-variable genes can be identified in silico as they contain easily recognised features, but genes controlled by phasevarions do not, complicating the rational design of vaccines. We have identified and begun to study phasevarions controlled by the switching of both Type I and Type III methyltransferases in several major veterinary bacterial pathogens; this talk will focus on our work to characterise these systems in the major pig pathogen Streptococcus suis. S. suis is also a major cause of bacterial meningitis in humans, particularly in S.E. Asia. Characterisation of a diverse collection of S. suis demonstrates that methyltransferases in this organism show a discrete lineage distribution. Pacific Biosciences SMRT sequencing and methylome analysis of multiple allelic variants of the Type III methyltransferase from S. suis, ModS, shows that different alleles methylate different target sequences. Proteomic analysis of enriched populations of S. suis encoding these different phase-variable Type III methyltransferases show these systems control different phasevarions, and influence major phenotypic differences. This analysis indicates the need for thorough characterisation of these systems in order to conclusively identify the stably expressed protein repertoire of S. suis and understand their role in pathobiology. This work will provide a framework for the rational design of vaccines and treatments against a major pathogen affecting both humans and animals.