In order to bind DNA, Cas9 and other CRISPR enzymes require a short PAM sequence adjacent to the targeted sequence at the locus of interest. SpCas9’s 3’ NGG PAM occurs frequently in GC-rich genomes, but a PAM is not always available near the locus you’d like to modify. To tackle the PAM problem, researchers have engineered alternative Cas9s binding distinct PAM sequences. Now, Hu et al., working in David Liu’s lab, have gone one step further, using directed evolution to create xCas9, an enzyme recognizing a broad range of PAMs like NG, GAA, and GAT, but also displaying increased editing specificity. We’re excited to learn more about xCas9 - here’s what we know so far!