CRISPR interference limits horizontal gene transfer (HGT) in staphylococci by targeting DNA. Researchers found that a CRISPR locus in *Staphylococcus epidermidis* strain RP62a prevents conjugation and plasmid transformation. The CRISPR system targets DNA directly, not mRNA, as shown by experiments where a self-splicing intron in the nes gene did not block interference, even when the target sequence was present in spliced mRNA. This suggests that CRISPR interference acts on DNA, not RNA. The study also demonstrated that CRISPR can prevent plasmid DNA transformation, as plasmids with intact target sequences were not transformed into RP62a, while those with mutated sequences were. These findings indicate that CRISPR systems can counteract multiple routes of plasmid transfer, including conjugation and transformation. The study provides strong evidence that CRISPR interference acts at the DNA level, differing from RNAi in eukaryotes. CRISPR systems may also prevent the spread of antibiotic resistance by targeting DNA sequences involved in HGT. The ability to target specific DNA sequences could have significant applications in controlling gene transfer in bacteria. The study highlights the broader role of CRISPR in preventing HGT and maintaining genetic identity, similar to restriction-modification systems. CRISPR interference is a powerful tool for controlling gene transfer in bacteria, with potential applications in combating antibiotic resistance.CRISPR interference limits horizontal gene transfer (HGT) in staphylococci by targeting DNA. Researchers found that a CRISPR locus in *Staphylococcus epidermidis* strain RP62a prevents conjugation and plasmid transformation. The CRISPR system targets DNA directly, not mRNA, as shown by experiments where a self-splicing intron in the nes gene did not block interference, even when the target sequence was present in spliced mRNA. This suggests that CRISPR interference acts on DNA, not RNA. The study also demonstrated that CRISPR can prevent plasmid DNA transformation, as plasmids with intact target sequences were not transformed into RP62a, while those with mutated sequences were. These findings indicate that CRISPR systems can counteract multiple routes of plasmid transfer, including conjugation and transformation. The study provides strong evidence that CRISPR interference acts at the DNA level, differing from RNAi in eukaryotes. CRISPR systems may also prevent the spread of antibiotic resistance by targeting DNA sequences involved in HGT. The ability to target specific DNA sequences could have significant applications in controlling gene transfer in bacteria. The study highlights the broader role of CRISPR in preventing HGT and maintaining genetic identity, similar to restriction-modification systems. CRISPR interference is a powerful tool for controlling gene transfer in bacteria, with potential applications in combating antibiotic resistance.