This study introduces a novel method for activating endogenous human genes using CRISPR-Cas9-based transcription factors. The researchers developed a dCas9-VP64 fusion protein, which is targeted to DNA sequences by guide RNA (gRNA) molecules. This system allows for the specific activation of endogenous target genes in human cells, demonstrating a simple and versatile approach for RNA-guided gene activation. The dCas9-VP64 fusion protein is designed to recognize promoter regions of target genes through hybridization of gRNA to specific DNA sequences, and its transactivation domain enhances gene expression. The study shows that co-expression of dCas9-VP64 with multiple gRNAs leads to robust activation of gene expression, as demonstrated by increased expression of the *IL1RN* gene and its product, IL-1ra. RNA-seq analysis confirmed that this activation is highly specific, with only the four isoforms of *IL1RN* showing significant expression changes. The system was also tested on other genes, including ASCL1, NANOG, HBG1/2, MYOD1, VEGFA, TERT, IL1B, and IL1R2, where co-transfection of dCas9-VP64 with gRNAs led to enhanced gene expression. The study highlights the potential of this system for various applications in gene therapy, genetic reprogramming, and regenerative medicine. The use of gRNAs allows for rapid and economical generation of new gene activators, as well as direct transfection of gRNAs into cells. The system is also applicable to other cell types, as demonstrated by successful activation of *ASCL1* in murine embryonic fibroblasts. The study also addresses the limitations of previous methods, such as the need for specialized expertise and the potential inefficiency of engineered proteins. The dCas9-VP64 system offers a more efficient and specific approach for gene activation, with the potential for future improvements in targeting multiple promoters and enhancing gene regulation. Overall, this study provides a new and effective method for activating endogenous genes using RNA-guided transcription factors, with potential applications in various areas of biotechnology and medicine.This study introduces a novel method for activating endogenous human genes using CRISPR-Cas9-based transcription factors. The researchers developed a dCas9-VP64 fusion protein, which is targeted to DNA sequences by guide RNA (gRNA) molecules. This system allows for the specific activation of endogenous target genes in human cells, demonstrating a simple and versatile approach for RNA-guided gene activation. The dCas9-VP64 fusion protein is designed to recognize promoter regions of target genes through hybridization of gRNA to specific DNA sequences, and its transactivation domain enhances gene expression. The study shows that co-expression of dCas9-VP64 with multiple gRNAs leads to robust activation of gene expression, as demonstrated by increased expression of the *IL1RN* gene and its product, IL-1ra. RNA-seq analysis confirmed that this activation is highly specific, with only the four isoforms of *IL1RN* showing significant expression changes. The system was also tested on other genes, including ASCL1, NANOG, HBG1/2, MYOD1, VEGFA, TERT, IL1B, and IL1R2, where co-transfection of dCas9-VP64 with gRNAs led to enhanced gene expression. The study highlights the potential of this system for various applications in gene therapy, genetic reprogramming, and regenerative medicine. The use of gRNAs allows for rapid and economical generation of new gene activators, as well as direct transfection of gRNAs into cells. The system is also applicable to other cell types, as demonstrated by successful activation of *ASCL1* in murine embryonic fibroblasts. The study also addresses the limitations of previous methods, such as the need for specialized expertise and the potential inefficiency of engineered proteins. The dCas9-VP64 system offers a more efficient and specific approach for gene activation, with the potential for future improvements in targeting multiple promoters and enhancing gene regulation. Overall, this study provides a new and effective method for activating endogenous genes using RNA-guided transcription factors, with potential applications in various areas of biotechnology and medicine.