The CRISPR/Cas9 system is a transformative gene editing technology with immense therapeutic potential for a broad spectrum of genetic disorders. Despite its promising capabilities, especially in ongoing cancer clinical trials, the safety concerns associated with off-target effects and the prohibitive costs—surpassing $2 million USD per treatment—remain significant hurdles. Addressing these challenges, our study involved an extensive chemical screening through which we identified a series of small-molecule Cas9 modulators. These modulators significantly enhance Cas9 specificity and efficiency, thus minimizing off-target risks. Our findings advocate for the integration of these chemical modulators into both genome and epigenome editing therapies, proposing a path toward more efficacious, safer, and economically viable gene therapies. Such innovations are crucial for expediting the clinical adoption of gene therapy