Generation of induced pluripotent stem cells typically requires the ectopic expression of transcription factors to reactivate the pluripotency network. However, it remains largely unclear what remodeling events on endogenous chromatin trigger reprogramming toward induced pluripotent stem cells (iPSCs). Toward this end, we employed CRISPR activation to precisely target and remodel endogenous gene loci of Oct4 and Sox2. Interestingly, we found that single-locus targeting of Sox2 was sufficient to remodel and activate Sox2, which was followed by the induction of other pluripotent genes and establishment of the pluripotency network. Simultaneous remodeling of the Oct4 promoter and enhancer also triggered reprogramming. Authentic pluripotent cell lines were established in both cases. Finally, we showed that targeted manipulation of histone acetylation at the Oct4 gene locus could also initiate reprogramming. Our study generated authentic iPSCs with CRISPR activation through precise epigenetic remodeling of endogenous loci and shed light on how targeted chromatin remodeling triggers pluripotency induction. Display omitted •Endogenous Oct4 and Sox2 can be targeted and activated by CRISPR activation•Activation of endogenous Oct4 or Sox2 triggers reprogramming to pluripotency•Oct4 promoter and enhancer are simultaneously remodeled by dCas9-SunTag-p300core•Authentic induced pluripotent stem cells are generated with CRISPR activation Ding and colleagues demonstrate that induced pluripotency can be achieved through targeted activation of endogenous Oct4 or Sox2 genes. With CRISPR activation, the promoter and enhancer are specifically remodeled, Oct4 or Sox2 is derepressed in fibroblasts, and reprogramming is triggered toward pluripotency.