Bacteria and archaea have been known for decades having evolved adaptive immune defenses called clustered regularly interspaced short palindromic repeats (CRISPR) /CRISPR-associated (Cas) systems to degrade foreign nucleic acids. Recently, these RNA-guided Cas9 nucleases derived from CRISPR/Cas systems have shown promise in transforming our ability to edit mammalian genomes. While zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) have shown similar promise, the ease of producing targeting RNAs over the generation of unique sequence-directed nucleases to guide site-specific modifications makes the CRISPR/Cas9 system an appealing method forgenomeediting. A shortguide RNA (sgRNA) candirectCas9 to a specific genomic sequence where it induces double-strand breaks that, when imperfectly repaired, yield mutations. Cas9 can also catalyze gene replacement through homologous recombination. Undoubtedly, Cas9-mediated genome editing and regulation should have transformative potential for basic science, genome engineering and therapeutics.