The ability to manipulate genomes has been significantly advanced by the development of the CRSIPR/Cas9 technology, in which the Cas9 endonuclease is targeted to specific sites in the genome by single-guide RNAs (sgRNA) - short sequences complementary to the genomic locus of interest. This approach has been further developed to allow regulation of gene expression at particular loci (a system referred to as CRISPRe): a catalytically inactive version of Cas9 (dCas9) can be fused to transcription activation (e.g. VP64) or repression (e.g. KRAB) domains and targeted to the desired genomic locus by sgRNA. Now, René Maehr and colleagues (p. 219) apply the CRISPRe system in human pluripotent stem cells. Their work provides a proof-of-principle that dCas9 fused to either VP64 or KRAB can regulate mRNA and protein levels of a gene targeted by sgRNA, with consequent effects on cell differentiation. This technique provides a widely applicable method to control gene expression, and hence manipulate cell fate, in stem cells.