The article describes the development and characterization of an improved transcriptional regulator, VP64-p65-Rta (VPR), which is a tripartite activator fused to nuclease-null Cas9. This fusion protein demonstrates enhanced transcriptional activation compared to the commonly used dCas9-VP64 activator. The study shows that VPR can activate both coding and non-coding genes in human HEK 293T cells, target multiple genes simultaneously, and stimulate neuronal differentiation of human induced pluripotent stem cells (iPSCs). The authors also demonstrate that VPR can be fused to other DNA-binding scaffolds, such as *Streptococcus thermophilus* (ST1)-dCas9, TALE, and zinc-finger proteins, to further enhance activation. The versatility and potency of VPR are further validated in yeast, Drosophila S2R+ cells, and *Mus musculus* Neuro-2A cells. The study highlights the importance of domain order and the potential for multiplexed activation using VPR, making it a powerful tool for gene induction and cellular reprogramming.The article describes the development and characterization of an improved transcriptional regulator, VP64-p65-Rta (VPR), which is a tripartite activator fused to nuclease-null Cas9. This fusion protein demonstrates enhanced transcriptional activation compared to the commonly used dCas9-VP64 activator. The study shows that VPR can activate both coding and non-coding genes in human HEK 293T cells, target multiple genes simultaneously, and stimulate neuronal differentiation of human induced pluripotent stem cells (iPSCs). The authors also demonstrate that VPR can be fused to other DNA-binding scaffolds, such as *Streptococcus thermophilus* (ST1)-dCas9, TALE, and zinc-finger proteins, to further enhance activation. The versatility and potency of VPR are further validated in yeast, Drosophila S2R+ cells, and *Mus musculus* Neuro-2A cells. The study highlights the importance of domain order and the potential for multiplexed activation using VPR, making it a powerful tool for gene induction and cellular reprogramming.