Synthetic transcription factors based on the RNA-guided CRISPR-Cas9 system are used to activate specific endogenous genes in human cells. Also online, Joung and colleagues report similar developments at two other loci. Technologies for engineering synthetic transcription factors have enabled many advances in medical and scientific research. In contrast to existing methods based on engineering of DNA-binding proteins, we created a Cas9-based transactivator that is targeted to DNA sequences by guide RNA molecules. Coexpression of this transactivator and combinations of guide RNAs in human cells induced specific expression of endogenous target genes, demonstrating a simple and versatile approach for RNA-guided gene activation.