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Natural genetic transformation and restriction-modification (R–M) systems play potentially antagonistic roles in bacteria. R–M systems, degrading foreign DNA to protect the cell from bacteriophage, can interfere with transformation, which relies on foreign DNA to promote genetic diversity. Here we describe how the human pathogen Streptococcus pneumoniae, which is naturally transformable, yet possesses either of two R–M systems, DpnI or DpnII, accommodates these conflicting processes. In addition to the classic restrictase and double-stranded DNA methylase, the DpnII system possesses an unusual single-stranded (ss) DNA methylase, DpnA, which is specifically induced during competence for genetic transformation. We provide further insight into our recent discovery that DpnA, which protects transforming foreign ssDNA from restriction, is crucial for acquisition of pathogenicity islands.