CRISPR-Cas systems are barriers to horizontal gene transfer (HGT) in bacteria. We use enterococci as models to understand the interactions of CRISPR-Cas with conjugative plasmids. Enterococcus faecalis,  a natural colonizer of the mammalian intestine, harbors pheromone-responsive plasmids (PRPs). PRPs mediate transfer of antibiotic resistance genes. We have observed striking differences in CRISPR-Cas efficiency in vitro versus in the intestine (Price et al. 2019). With this knowledge, we developed a PRP based method for disseminating an engineered CRISPR-Cas system to target antibiotic resistant enterococci. CRISPR-Cas encoding PRPs can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner (Rodrigues et al. 2019). Our results demonstrate that standard in vitro experiments poorly model the native in vivo anti-plasmid activity of CRISPR-Cas. Our work demonstrates that barriers to HGT can have a strong impact on in vivo antibiotic resistance dissemination and that engineered CRISPR-Cas systems hold promise for precision microbiome engineering and other microbiology applications (Palacios Araya et al. 2021).