This study investigates the genome-wide binding of a catalytically inactive Cas9 (dCas9) from *Streptococcus pyogenes* loaded with single guide RNAs (sgRNAs) in mouse embryonic stem cells (mESCs). The researchers found that each of the four sgRNAs tested targets dCas9 to tens to thousands of genomic sites, characterized by a 5-nucleotide seed region in the sgRNA, in addition to an NGG protospacer adjacent motif (PAM). Chromatin inaccessibility prevents dCas9 binding to other sites with matching seed sequences, and 70% of off-target sites are associated with genes. Targeted sequencing of 295 dCas9 binding sites in mESCs transfected with catalytically active Cas9 identified only one site mutated above background. The study proposes a two-state model for Cas9, where a seed match triggers binding but extensive pairing with target DNA is required for cleavage. The findings explain previous observations of heterogeneity in target recognition and cleavage, providing insights into the mechanism of Cas9 and guiding future target design.This study investigates the genome-wide binding of a catalytically inactive Cas9 (dCas9) from *Streptococcus pyogenes* loaded with single guide RNAs (sgRNAs) in mouse embryonic stem cells (mESCs). The researchers found that each of the four sgRNAs tested targets dCas9 to tens to thousands of genomic sites, characterized by a 5-nucleotide seed region in the sgRNA, in addition to an NGG protospacer adjacent motif (PAM). Chromatin inaccessibility prevents dCas9 binding to other sites with matching seed sequences, and 70% of off-target sites are associated with genes. Targeted sequencing of 295 dCas9 binding sites in mESCs transfected with catalytically active Cas9 identified only one site mutated above background. The study proposes a two-state model for Cas9, where a seed match triggers binding but extensive pairing with target DNA is required for cleavage. The findings explain previous observations of heterogeneity in target recognition and cleavage, providing insights into the mechanism of Cas9 and guiding future target design.