The study by Marraffini and Sontheimer investigates the role of CRISPR loci in preventing horizontal gene transfer (HGT) in *Staphylococcus epidermidis*. CRISPR loci, which are present in many bacterial and archaeal genomes, confer sequence-directed immunity against phage infections through the production of small CRISPR RNAs (crRNAs) that target and interfere with phage DNA. The authors focus on a clinical isolate of *S. epidermidis* that contains a CRISPR spacer matching the *nickase* gene found in staphylococcal conjugative plasmids, which are important for the spread of antibiotic resistance. The researchers demonstrate that CRISPR interference prevents plasmid conjugation and transformation in *S. epidermidis*. They show that the interference mechanism targets DNA directly, as inserting a self-splicing intron into the *nickase* gene blocks interference despite the target sequence being present in the spliced mRNA. This indicates that the CRISPR system acts at the DNA level, rather than targeting RNA transcripts. further, the authors test the requirement for *nickase* activity and mRNA expression, finding that interference is independent of mRNA but requires an intact target sequence in the plasmid DNA. They also show that CRISPR interference can prevent plasmid transformation, suggesting that it counteracts multiple routes of HGT. The findings highlight the potential of CRISPR systems to limit the spread of antibiotic resistance and other genetic elements in pathogenic bacteria, providing a mechanism for controlling the horizontal transfer of genes.The study by Marraffini and Sontheimer investigates the role of CRISPR loci in preventing horizontal gene transfer (HGT) in *Staphylococcus epidermidis*. CRISPR loci, which are present in many bacterial and archaeal genomes, confer sequence-directed immunity against phage infections through the production of small CRISPR RNAs (crRNAs) that target and interfere with phage DNA. The authors focus on a clinical isolate of *S. epidermidis* that contains a CRISPR spacer matching the *nickase* gene found in staphylococcal conjugative plasmids, which are important for the spread of antibiotic resistance. The researchers demonstrate that CRISPR interference prevents plasmid conjugation and transformation in *S. epidermidis*. They show that the interference mechanism targets DNA directly, as inserting a self-splicing intron into the *nickase* gene blocks interference despite the target sequence being present in the spliced mRNA. This indicates that the CRISPR system acts at the DNA level, rather than targeting RNA transcripts. further, the authors test the requirement for *nickase* activity and mRNA expression, finding that interference is independent of mRNA but requires an intact target sequence in the plasmid DNA. They also show that CRISPR interference can prevent plasmid transformation, suggesting that it counteracts multiple routes of HGT. The findings highlight the potential of CRISPR systems to limit the spread of antibiotic resistance and other genetic elements in pathogenic bacteria, providing a mechanism for controlling the horizontal transfer of genes.